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Medical Headline Misinformation Strikes Again: Claims About Vitamin D

Posted in Academic Publishing, Biological Networks, Bone Disease and Musculoskeletal Disease, Ca2+ triggered activation, Calcium, Calcium Signaling, Cancer and Current Therapeutics, Cancer Prevention: Research & Programs, Cardiac & Vascular Repair Tools Subsegment, Cell Biology, Diabetes Mellitus, Drug Toxicity, Endocrine Diseases, Health Economics and Outcomes Research, Peripheral Arterial Disease & Peripheral Vascular Surgery, Population Health Management, tagged , , , , , , , , , , , , , on April 14, 2015| Leave a Comment »

Medical Headline Misinformation Strikes Again: Claims About Vitamin D

Reporter: Stephen J. Williams, Ph.D.

A recent posting by a group called the Vitamin D Council (and put on this site) had referred to, and misquoted, the Mayo Clinic site on the role of vitamin D on various diseases. At first I was curious if this was actually reported on the Mayo site on claims of prevention of various cancers (as results from retrospective studies had been conflicting) and originally had made some strong comments. From comments made from this post I do agree that there is strong evidence about vitamin D supplementation for the prevention of rickets but as Mayo reviewed claims about vitamin D supplementation and prevention of certain diseases such as cancers and heart disease may not be as strong as some suggest.  My main concern was : is the clinical evidence strong enough for the role of vitamin D supplementation in a wide array of diseases and did Mayo make the claims as suggested in some media reports?  Actually Mayo does a very thorough job of determining the clinical evidence and the focus of vitamins and cancer risk will be a point of further discussion.

After consulting the Mayo clinic website it appears that the Vitamin D Council site had indeed misquoted and misrepresented the medical information contained within the Mayo Clinic website.

Medical Misinformation Is Probably The Most Hazardous and Biggest Risk Impacting a Healthy Lifestyle

The site had made numerous claims on role of vitamin D3 (cholecalciferol) in numerous diseases; making it appear there were definitive links between low vitamin D3 and risk of hypertension, cancer, depression and diabetes.

A little background on Vitamin D

From Wikipedia

Vitamin D refers to a group of fat-soluble secosteroids responsible for enhancing intestinal absorption of calcium, iron, magnesium, phosphate and zinc. In humans, the most important compounds in this group are vitamin D3 (also known as cholecalciferol) and vitamin D2 (ergocalciferol).[1] Cholecalciferol and ergocalciferol can be ingested from the diet and from supplements.[1][2][3] Very few foods contain vitamin D; synthesis of vitamin D (specifically cholecalciferol) in the skin is the major natural sources of the vitamin. Dermal synthesis of vitamin D from cholesterol is dependent on sun exposure (specifically UVB radiation).Vitamin D has a significant role in calcium homeostasis and metabolism. Its discovery was due to effort to find the dietary substance lacking in rickets (the childhood form of osteomalacia).[4]

also from Widipedia on Vitamin D toxicity

Vitamin D toxicity

Vitamin D toxicity is rare.[20] It is caused by supplementing with high doses of vitamin D rather than sunlight. The threshold for vitamin D toxicity has not been established; however, the tolerable upper intake level (UL), according to some research, is 4,000 IU/day for ages 9–71.[7] Whereas another research concludes that in healthy adults, sustained intake of more than 1250 μg/day (50,000 IU) can produce overt toxicity after several months and can increase serum 25-hydroxyvitamin D levels to 150 ng/ml and greater;[20][56] those with certain medical conditions, such as primary hyperparathyroidism,[57] are far more sensitive to vitamin D and develop hypercalcemia in response to any increase in vitamin D nutrition, while maternal hypercalcemia during pregnancy may increase fetal sensitivity to effects of vitamin D and lead to a syndrome of mental retardation and facial deformities.[57][58]

After being commissioned by the Canadian and American governments, the Institute of Medicine (IOM) as of 30 November 2010, has increased the tolerable upper limit (UL) to 2,500 IU per day for ages 1–3 years, 3,000 IU per day for ages 4–8 years and 4,000 IU per day for ages 9–71+ years (including pregnant or lactating women).[7]

Published cases of toxicity involving hypercalcemia in which the vitamin D dose and the 25-hydroxy-vitamin D levels are known all involve an intake of ≥40,000 IU (1,000 μg) per day.[57] Recommending supplementation, when those supposedly in need of it are labeled healthy, has proved contentious, and doubt exists concerning long-term effects of attaining and maintaining high serum 25(OH)D by supplementation.[61]

From the Mayo Clinic Website on Vitamin D

The Mayo Clinic has done a wonderful job curating the uses and proposed uses of vitamin D for various diseases and rates the evidence using a grading system A-F (as shown below):

Key to grades

A STRONG scientific evidence FOR THIS USE

B GOOD scientific evidence FOR THIS USE

C UNCLEAR scientific evidence for this use

D Fair scientific evidence AGAINST THIS USE (it may not work)

F Strong scientific evidence AGAINST THIS USE (it likely does not work)

Mayo has information for other natural products as well. As described below (and on the Mayo site here) most of the supposed evidence fails their criteria for a strong clinical link between diseases such as heart disease, hypertension, cancer and vitamin D (either parental or D3) levels.

The important take-home from the Mayo site is that there is strong evidence for the use of vitamin D in diseases related to the known mechanism of vitamin D such as low serum phosphate either due to kidney disease (Fanconi syndrome) or familial hypophosphatemia or in diseases surrounding bone metabolism like osteomalacia, rickets, dental cavities and even as a treatment for psoriasis or underactive parathyroid.

However most indications like hypertension, stroke, cancer prevention or treatment (other than supportive therapy for low vitamin D levels) get a poor grade (C or D) for clinical correlation from Mayo Clinic.

A Post in the Near Future will be a Curation of Validated Clinical Studies on Effects of Vitamins on Cancer Risk.

Below is taken from the Mayo Site:

Evidence

These uses have been tested in humans or animals.  Safety and effectiveness have not always been proven.  Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.

Grading rationale

Evidence grade Condition to which grade level applies
A

Deficiency (phosphate)

Familial hypophosphatemia is a rare, inherited condition in which there are low blood levels of phosphate and problems with vitamin D metabolism. It is a form of rickets. Taking calcitriol or dihydrotachysterol by mouth along with phosphate supplements is effective for treating bone disorders in people with this disease. Those with this disorder should be monitored by a medical professional.
A

Kidney disease (causing low phosphate levels)

Fanconi syndrome is a kidney disease in which nutrients, including phosphate, are lost in the urine instead of being reabsorbed by the body. Taking ergocalciferol by mouth is effective for treating low phosphate levels caused by Fanconi syndrome.
A

Osteomalacia (bone softening in adults)

Adults who have severe vitamin D deficiency may experience bone pain and softness, as well as muscle weakness. Osteomalacia may be found among the following people: those who are elderly and have diets low in vitamin D; those with problems absorbing vitamin D; those without enough sun exposure; those who undergo stomach or intestine surgery; those with bone disease caused by aluminum; those with chronic liver disease; or those with bone disease associated with kidney problems. Treatment for osteomalacia depends on the cause of the disease and often includes pain control and surgery, as well as vitamin D and phosphate-binding agents.
A

Psoriasis (disorder causing skin redness and irritation)

Many different approaches are used to treat psoriasis, including light therapy, stress reduction, moisturizers, or salicylic acid. For more severe cases, calcipotriene (Dovonex®), a man-made substance similar to vitamin D3, may help control skin cell growth. This agent is a first-line treatment for mild-to-moderate psoriasis. Calcipotriene is also available with betamethasone and may be safe for up to one year. Vitamin D3 (tacalcitol) ointment or high doses of becocalcidiol applied to the skin are also thought to be safe and well-tolerated.
A

Rickets (bone weakening in children)

Rickets may develop in children who have vitamin D deficiency caused by a diet low in vitamin D, a lack of sunlight, or both. Babies fed only breast milk (without supplemental vitamin D) may also develop rickets. Ergocalciferol or cholecalciferol is effective for treating rickets caused by vitamin D deficiency. Calcitriol should be used in those with kidney failure. Treatment should be under medical supervision.
A

Thyroid conditions (causing low calcium levels)

Low levels of parathyroid hormone may occur after surgery to remove the parathyroid glands. Taking high doses of dihydrotachysterol, calcitriol, or ergocalciferol by mouth, with or without calcium, may help increase calcium levels in people with this type of thyroid problem. Increasing calcium intake, with or without vitamin D, may reduce the risk of underactive parathyroid glands.
A

Thyroid conditions (due to low vitamin D levels)

Some people may have overactive parathyroid glands due to low levels of vitamin D, and vitamin D is the first treatment for this disorder. For people who have overactive parathyroid glands due to other causes, surgery to remove the glands is often recommended. Studies suggest that vitamin D may help reduce the risk of further thyroid problems after undergoing partial or total removal of the parathyroid glands.
A

Vitamin D deficiency

Vitamin D deficiency is associated with many conditions, including bone loss, kidney disease, lung disorders, diabetes, stomach and intestine problems, and heart disease. Vitamin D supplementation has been found to help prevent or treat vitamin D deficiency.
B

Dental cavities

Much evidence has shown that vitamin D helps prevent cavities; however, more high-quality research is needed to further support this finding.
B

Renal osteodystrophy (bone problems due to chronic kidney failure)

Renal osteodystrophy refers to the bone problems that occur in people with chronic kidney failure. Calcifediol or ergocalciferol taken by mouth may help prevent this condition in people with chronic kidney failure who are undergoing treatment.
C

Autoimmune diseases

Vitamin D may reduce inflammation and help prevent autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, and Crohn’s disease. However, further high-quality research is needed to confirm these results.
C

Bone density (children)

Vitamin D improves bone density in children who are vitamin D deficient. However, results are unclear and more research is needed.
C

Bone diseases (kidney disease or kidney transplant)

Vitamin D has been studied for people with chronic kidney disease. The use of substances similar to vitamin D has been found to increase bone density in people with kidney disease. The effect of vitamin D itself is unclear. Further research is needed before conclusions can be made.
C

Cancer prevention (breast, colorectal, prostate, other)

Many studies have looked at the effects of vitamin D on cancer. Positive results have been reported with the use of vitamin D alone or with calcium. Vitamin D intake with or without calcium has been studied for colorectal, cervical, breast, and prostate cancer. A reduced risk of colorectal cancer has been shown with vitamin D supplementation. However, there is a lack of consistent or strong evidence. Further study is needed.
C

Fibromyalgia (long-term, body-wide pain)

Vitamin D has been studied for the treatment of fibromyalgia, but evidence is lacking in support of its effectiveness. Further study is needed.
C

Fractures (prevention)

Conflicting results have been found on the use of vitamin D for fracture prevention. The combination of alfacalcidol and alendronate has been found to reduce the risk of falls and fractures. However, further high-quality research is needed before firm conclusions can be made.
C

Hepatic osteodystrophy (bone disease in people with liver disease)

Metabolic bone disease is common among people with chronic liver disease, and osteoporosis accounts for the majority of cases. Varying degrees of poor calcium absorption may occur in people with chronic liver disease due to malnutrition and vitamin D deficiency. Vitamin D taken by mouth or injected may play a role in the management of this condition.
C

High blood pressure

Low levels of vitamin D may be linked to high blood pressure. Blood pressure is often higher during the winter season, at a further distance from the equator, and in people with dark skin pigmentation. However, the evidence is unclear. More research is needed in this area. People who have high blood pressure should be managed by a medical professional.
C

Immune function

Early research suggests that vitamin D and similar compounds, such as alfacalcidol, may impact immune function. Vitamin D added to standard therapy may benefit people with infectious disease. More studies are needed to confirm these results.
C

Seasonal affective disorder (SAD)

SAD is a form of depression that occurs during the winter months, possibly due to reduced exposure to sunlight. In one study, vitamin D was found to be better than light therapy in the treatment of SAD. Further studies are necessary to confirm these findings.
C

Stroke

Higher levels of vitamin D may decrease the risk of stroke. However, further study is needed to confirm the use of vitamin D for this condition.
C

Type 1 diabetes

Some studies suggest that vitamin D may help prevent the development of type 1 diabetes. However, there is a lack of strong evidence to support this finding.
C

Type 2 diabetes

Vitamin D has mixed effects on blood sugar and insulin sensitivity. It is often studied in combination with calcium. Further research is needed to confirm these results.
D

Cancer treatment (prostate)

Evidence suggests a lack of effect of vitamin D as a part of cancer treatment for prostate cancer. Further study is needed using other formulations of vitamin D and other types of cancer.
D

Heart disease

Vitamin D is recognized as being important for heart health. Overall, research is not consistent, and some studies have found negative effects of vitamin D on heart health. More high-quality research is needed to make a firm conclusion.
D

High cholesterol

Many studies have looked at the effects of vitamin D alone or in combination with other agents for high cholesterol, but results are inconsistent. Some negative effects have been reported. More research is needed on the use of vitamin D alone or in combination with calcium.

Other related articles on Vitamins and Disease were published in this Open Access Online Scientific Journal, include the following:

Multivitamins – Don’t help Extend Life or ward off Heart Disease and Improve state of Memory Loss

Diet and Diabetes

What do you know about Plants and Neutraceuticals?

Malnutrition in India, high newborn death rate and stunting of children age under five years

Omega-3 fatty acids, depleting the source, and protein insufficiency in renal disease

American Diet is LOW in four important Nutrients that have a direct bearing on Aging and the Brain

Parathyroids and Bone Metabolism

Read Full Post »

Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism

Posted in Calcium Signaling, Cell Biology, Signaling & Cell Circuits, Cytoskeleton, Electrophysiology, Frontiers in Cardiology and Cardiovascular Disorders, Origins of Cardiovascular Disease, tagged , , , , , , , , , on September 12, 2013| 22 Comments »

Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism

 

Author, Introduction: Larry H Bernstein, MD, FCAP

Author, Summary: Justin Pearlman, MD, PhD, FACC 

and

Article Curator: Aviva Lev-Ari, PhD, RN

Article VIII Disruption of Calcium Homeostasis Cardiomyocytes and Vascular Smooth Muscle Cells The Cardiac and Cardiovascular Calcium Signaling Mechanism

Image created by Adina Hazan 06/30/2021

This article is the Part VIII in a series of articles on Activation and Dysfunction of the Calcium Release Mechanisms in Cardiomyocytes and Vascular Smooth Muscle Cells. Calcium has a storage and release cycle that flags activation of important cellular activities that include in particular the cycle activation of muscle contraction both to circulate blood and control its pressure and distribution. Homeostasis – the maintenance of status – requires controlled release of calcium from storage and return of calcium to storage. Such controls are critical both within cells, and for the entire biologic system. Thus the role of kidneys in maintaining the correct total body load of available calcium is just as vital as the subcellular systems of calcium handling in heart muscle and in the muscles that line arteries to control blood flow. The practical side to this knowledge includes not only identifying abnormalities at the cellular as well as system levels, but also identifying better opportunities to characterize disease and to intervene.

The Series consists of the following articles:

Part I: Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/

Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/

Part III: Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD
 and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/02/renal-distal-tubular-ca2-exchange-mechanism-in-health-and-disease/

Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-differences/

Part V: Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter

Larry H Bernstein, MD, FCAP
and
Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/23/calmodulin-and-protein-kinase-c-drive-the-ca2-regulation-of-hormone-and-neurotransmitter-release-that-triggers-ca2-stimulated-exocytosis/

Part VI: Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-contractile/

Part VIII: Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

Part IX: Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Part X: Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/

Part XI: Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/11/01/sensors-and-signaling-in-oxidative-stress/

Part XII: Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/21/genetic-polymorphisms-of-ion-channels-have-a-role-in-the-pathogenesis-of-coronary-microvascular-dysfunction-and-ischemic-heart-disease/

This article has three Sections:

Section One:

Vascular Smooth Muscle Cells: The Cardiovascular Calcium Signaling Mechanism

Section Two:

Cardiomyocytes Cells: The Cardiac Calcium Signaling Mechanism

Section Three:

The Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Introduction

by Larry H Bernstein, MD, FACC   

Introduction

This discussion in two Sections brings to a conclusion the two main aspects of calcium signaling and transient current induction in the cardiovascular system – involving vascular smooth muscle and cardiomyocyte.  In this first Section, it extends the view of smooth muscle beyond the vascular smooth muscle to contraction events in gastrointestinal tract, urinary bladder, and uterus, but by inference, to ductal structures (gallbladder, parotid gland, etc.).  This discussion also reinforces the ECONOMY of the evolutionary development of these functional MOTIFS, as a common thread is used again, and again, in specific contexts.  The main elements of this mechanistic framework are:

  • the endoplasmic (sarcoplasmic) reticulum as a strorage depot for calcium needed in E-C coupling
  • the release of Ca(2+) into the cytoplasm
  • the generation of a voltage and current with contraction of the muscle cell unit
  • the coordination of smooth muscle cell contractions (in waves)
    • this appears to be related to the Rho/Rho kinase pathway
  • there is also a membrane depolarization inherent in the activation mechanism
  • whether there is an ordered relationship between the calcium release and the membrane polarization, and why this would be so, in not clear
  • three different models of calcium release are shown from the MJ Berridge classification article below in Figure 1.
  • Model C is of special interest because of the focus on cytosolic (Ca+) ion transfers involving the interstitial cells of Cajal (Ramin e’ Cajal) through gap junctions

Santiago Ramón y Cajal  (Spanish: [sanˈtjaɣo raˈmon i kaˈxal]; 1 May 1852 – 18 October 1934) was a Spanish pathologist, histologist and neuroscientist. He was awarded  the Nobel Prize in Physiology or Medicine in 1906 together with Italian Camillo Golgi “in recognition of their work on the structure of the nervous system”.  Relevant to this discussion, he discovered a new type of cell, to be named after him: the interstitial cell of Cajal (ICC). This cell is found interleaved among neurons embedded within the smooth muscles lining the gut, serving as the generator and pacemaker of the slow waves of contraction that move material along the gastrointestine, vitally mediating neurotransmission from motor nerves to smooth muscle cells . Cajal also described in 1891 slender horizontal bipolar cells in the developing marginal zone of lagomorphs.(See the Cajal’s original drawing of the cells) , considered by Retzius as homologues to the cells he found in humans and in other mammals (Retzius, 1893, 1894).  The term Cajal–Retzius cell is applied to reelin-producing neurons of the human embryonic marginal zone.  

240px-Cajal-Retzius_cell_drawing_by_Cajal_1891

Section One

Vascular Smooth Muscle Cells: The Cardiovascular Calcium Signaling Mechanism

Smooth Muscle Cell Calcium Activation Mechanisms

Michael J. Berridge

J Physiol 586.21 (2008) pp 5047–5061

http://jp.physoc.org/content/586/21/5047.full.pdf

Classification of Smooth Muscle Ca2+ Activation Mechanisms

Excitation–contraction coupling in SMCs occurs through two main mechanisms. Many SMCs are activated by Ca2+ signalling cascades (Haddock & Hill, 2005; Wray et al.  2005).  In addition, there is a Rho/Rho kinase signaling pathway that acts by altering the Ca2+ sensitivity of the contractile system (Somlyo & Somlyo, 2003). Since the latter appears to have more of a modulatory function,most attention will focus on how Ca2+ signalling is activated.  Since membrane depolarization is a key element for the activation of many SMCs,much attention will focus on the mechanisms responsible for depolarizing the membrane.  However, there are other SMCs where activation depends on the periodic release of Ca2+ from internal stores. These different Ca2+ activation mechanisms fall into the following three main groups (Fig. 1).

 

Fig 1 Ca2+

Figure 1. The three main mechanisms responsible for generating the Ca2+ transients that trigger smooth

muscle cell (SMC) contraction

A, receptor-operated channels (ROCs) or a membrane oscillator induces the membrane depolarization (_V) that

triggers Ca2+ entry and contraction.

B, a cytosolic Ca2+ oscillator induces the Ca2+ signal that drives contraction.

C, a cytosolic Ca2+ oscillator in interstitial cells of Cajal (ICCs) or atypical SMCs induces the membrane depolarization

that spreads through the gap junctions to activate neighbouring SMCs. Reproduced from Berridge (2008), with permission

SOURCE for Figure 1: J Physiol 586.21 M. J. Berridge Smooth muscle cell calcium activation mechanisms 5048

http://jp.physoc.org/content/586/21/5047.full.pdf

Mechanism A.

Many SMCs are activated by membrane depolarization (_V) that opens L-type voltage-operated channels (VOCs) allowing external Ca2+ to flood into the cell to trigger contraction. This depolarization is induced either by ionotropic receptors (vas deferens) or a membrane oscillator (bladder and uterus). Themembrane oscillator, which resides in the plasma membrane, generates the periodic pacemaker depolarizations responsible for the action potentials that drive contraction. The depolarizing signal that activates gastrointestinal, urethral and ureter SMCs is described in mechanism C.

Mechanism B.

The rhythmical contractions of vascular, lymphatic, airway and corpus cavernosum SMCs depend on an endogenous pacemaker driven by a cytosolic Ca2+ oscillator that is responsible for the periodic release of Ca2+  from the endoplasmic reticulum. The periodic pulses of Ca2+ often cause membrane depolarization, but this is not part of the primary activation mechanism but has a secondary role to synchronize and amplify the oscillatory mechanism. Neurotransmitters and hormones act by modulating the frequency of the cytosolic oscillator.

Mechanism C.

A number of SMCs are activated by pacemaker cells such as the interstitial cells of Cajal (ICCs)  (gastrointestinal and urethral SMCs) or atypical SMCs (ureter). These pacemaker cells have a cytosolic oscillator that generates the repetitive Ca2+  transients that activate inward currents that spread through the gap junctions to provide the depolarizing signal (_V) that triggers contraction through mechanism A.  In the following sections, some selected SMC types will illustrate how these signalling mechanisms have been adapted to control different contractile functions with particular emphasis on how Ca2+ signals are activated.

Vascular, Lymphatic and Airway Smooth Muscle Cells

Vascular, lymphatic and airway smooth muscle, which generate rhythmical contractions over an extended period of time, have an endogenous pacemaker mechanism driven by a cytosolic Ca2+ oscillator. In addition, these SMCs also respond to neurotransmitters released from the neural innervation. In the case of mesenteric arteries, the perivascular nerves release both ATP and noradrenaline  (NA). The ATP acts first to produce a small initial contraction that is then followed by a much larger contraction when NA initiates a series of Ca2+ transients (Lamont et al. 2003). Such agonist-induced Ca2+ oscillations are a characteristic feature of the activation mechanisms of vascular (Iino et al. 1994; Lee et al.  2001; Peng et al. 2001; Perez & Sanderson, 2005b; Shaw et al. 2004) and airway SMCs (Kuo et al. 2003; Perez & Sanderson, 2005a; Sanderson et al. 2008). In some blood vessels, a specific tone is maintained by the spatial averaging of asynchronous oscillations. However, there are some vessels where the oscillations in groups of cells are synchronized resulting in the pulsatile contractions known as vasomotion (Mauban et al. 2001; Peng et al.  2001; Lamboley et al. 2003; Haddock & Hill, 2005).  Such vasomotion is also a feature of lymphatic vessels (Imtiaz et al. 2007). Another feature of this oscillatory activity is that variations in transmitter concentration are translated into a change in contractile tone through a mechanism of frequency modulation (Iino et al.  1994; Kuo et al. 2003; Perez & Sanderson, 2005a,b).  Frequency modulation is one of the mechanisms used for encoding and decoding signalling information through Ca2+ oscillations (Berridge, 2007).

The periodic pulses of Ca2+ that drive these rhythmical SMCs are derived from the internal stores through the operation of a cytosolic Ca2+  oscillator (Haddock & Hill, 2005; Imtiaz et al. 2007;  Sanderson et al. 2008). The following general model, which applies to vascular, lymphatic, airway and perhaps also to corpus cavernosum SMCs, attempts to describe the nature of this oscillator and how it can be induced or modulated by neurotransmitters. A luminal loading Ca2+ oscillation mechanism (Berridge & Dupont, 1994; Berridge, 2007)  forms the basis of this cytosolic oscillator model that depends upon the following sequential series of events  (Fig. 5).

 Fig 2 Ca2+

Figure 5. Vascular or airway SMCs are driven by a cytosolic oscillator that generates a periodic release

of Ca2+ from the endoplasmic reticulum that usually appears as a propagating Ca2+ wave

The oscillator is induced/modulated by neurotransmitters such as acetylcholine (ACh), 5-hydroxytryptamine (5-HT),

noradrenaline (NA) and endothelin-1 (ET-1), which act through inositol 1,4,5-trisphosphate (InsP3) that initiates

the oscillatory mechanism. The sequence of steps 1–9 is described in the text. Reproduced from Berridge (2008),

with permission.

SOURCE for Figure 5: J Physiol 586.21 M. J. Berridge Smooth muscle cell calcium activation mechanisms 5053

http://jp.physoc.org/content/586/21/5047.full.pdf

For Disruption of Calcium Homeostasis in Vascular Smooth Muscle Cells, see

Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-differen/

Part V: Heart, Vascular Smooth Muscle, Excitation-Contraction Coupling (E-CC), Cytoskeleton, Cellular Dynamics and Ca2 Signaling

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/26/heart-smooth-muscle-excitation-contraction-coupling-cytoskeleton-cellular-dynamics-and-ca2-signaling/

 

Section Two

Cardiomyocytes Cells: The Cardiac Calcium Signaling Mechanism

Cardiomyocytes and Ca2+ Channels

Published August 8, 2011 // JCB vol. 194 no. 3 355-365 
The Rockefeller University Press, doi: 10.1083/jcb.201101100

Cellular mechanisms of cardiomyopathy
  1. Pamela A. Harvey and
  2. Leslie A. Leinwand

+Author Affiliations


  1. Department of Molecular, Cellular, and Developmental Biology, University of Colorado at Boulder, Boulder, CO 80309
  1. Correspondence to Leslie Leinwand: leslie.leinwand@colorado.edu

Abbreviations

DCM dilated cardiomyopathy

HCM hypertrophic cardiomyopathy

MyH Cmyosin heavy chain

RCM restrictive cardiomyopathy

Introduction

The heart relies on a complex network of cells to maintain appropriate function. Cardiomyocytes, the contracting cells in the heart, exist in a three-dimensional network of endothelial cells, vascular smooth muscle, and an abundance of fibroblasts as well as transient populations of immune cells. Gap junctions electrochemically coordinate the contraction of individual cardiomyocytes, and their connection to the extracellular matrix (ECM) transduces force and coordinates the overall contraction of the heart. Intracellularly, repeating units of actin and myosin form the backbone of sarcomere structure, the basic functional unit of the cardiomyocyte (Fig. 1). The sarcomere itself consists of ∼20 proteins; however, more than 20 other proteins form connections between the myocytes and the ECM and regulate muscle contraction (Fig. 1 B). Given the complexity of the coordinated efforts of the many proteins that exist in multimeric complexes, dysfunction occurs when these interactions are disrupted.

Figure 1.

View larger version:

Figure 1. Anatomy of the cardiac sarcomere(A) Diagram of the basic organization of the sarcomere. The sarcomere forms the basic contractile unit in the cardiomyocytes of the heart. Thin filaments composed of actin are anchored at the Z line and form transient sliding interactions with thick filaments composed of myosin molecules. The M Line, I Band, and A Band are anatomical features defined by their components (actin, myosin, and cytoskeletal proteins) and appearance in polarized light. Titin connects the Z line with the M line and contributes to the elastic properties and force production of the sarcomere through its extensible region in the I Band. Coordinated shortening of the sarcomere creates contraction of the cardiomyocyte. (B) Representation of the major proteins of the cardiac sarcomere. Attachment to the ECM is mediated by costameres composed of the dystroglycan–glycoprotein complex and the integrin complex. Force transduction and intracellular signaling are coordinated through the costamere. The unique roles of each of these proteins are critical to appropriate function of the heart. T-cap, titin cap; MyBP-C, myosin-binding protein C; NOS, nitric oxide synthase.

Although the heart may functionally tolerate a variety of pathological insults, adaptive responses that aim to maintain function eventually fail, resulting in a wide range of functional deficits or cardiomyopathy. Although a multitude of intrinsic and extrinsic stimuli promote cardiomyopathies, the best described causes are the >900 mutations in genes expressed in the cardiomyocyte (Fig. 1 B; Wang et al., 2010). Mutations in most of these genes cause a diverse range of cardiomyopathies, many with overlapping clinical phenotypes. Mutations in sarcomeric genes are usually inherited in an autosomal-dominant manner and are missense mutations that are incorporated into sarcomeres (Seidman and Seidman, 2001). Thus far >400 mutations in 13 sarcomeric proteins including β-myosin heavy chain (β-MyHC), α-cardiac actin, tropomyosin, and troponin have been associated with cardiomyopathy (www.cardiogenomics.med.harvard.edu). Table I summarizes these mutated proteins.

Ca2+ regulation and calcineurin signaling

Ca2+ concentrations inside the cardiomyocyte are critically important to actin–myosin interactions. Ca2+ is sequestered within the sarcoplasmic reticulum and the sarcomere itself, which serves as an intracellular reserve that is released in response to electrical stimulation of the cardiomyocyte. After contraction, sarco/endoplasmic reticulum Ca2+-ATPase sequesters the Ca2+ back into the sarcoplasmic reticulum to restore Ca2+balance. There is a clear correlation between force production and perturbation of Ca2+regulation, alterations of which might directly induce pathological, anatomical, and functional alterations that lead to heart failure via activation of GPCRs (Minamisawa et al., 1999).

Ca2+ in the cytosol can be increased to modulate sarcomere contractility by signaling through Gαq recruitment and activation of PLCβ. Ca2+ released from the sarcoplasmic reticulum activates calmodulin, which phosphorylates calcineurin, a serine/threonine phosphatase. Upon activation, calcineurin interacts with and dephosphorylates nuclear factor of activated T cells (NFAT), which then translocates into the nucleus. Calcineurin activation exacerbates hypertrophic signals and expedites the transition to a decompensatory state. Indeed, cardiac-specific overexpression of calcineurin or NFAT leads to significant cardiac hypertrophy that progresses rapidly to heart failure (Molkentin et al., 1998). Administration of antagonists of calcineurin attenuates the hypertrophic response of neonatal rat ventricular myocytes to stimuli such as phenylephrine (PE) and angiotensin II (Taigen et al., 2000).

Mechanotransduction and signaling in the cardiomyocyte

The responses of cardiomyocytes to systemic stress or genetic abnormalities are modulated by mechanosensitive mechanisms within the cardiomyocyte (Molkentin and Dorn, 2001; Seidman and Seidman, 2001; Frey and Olson, 2003). A complex network of proteins that connects the sarcomere to the ECM forms the basis of the mechanotransduction apparatus. For example, components of the costamere complex, which form the connection between the sarcomere and the ECM via integrins, initiate intracellular signaling and subsequently alter contractile properties and transcriptional regulation in response to membrane distortion. Mechanosensitive ion channels are also implicated in signal initiation in response to systemic stress (Le Guennec et al., 1990;Zhang et al., 2000; de Jonge et al., 2002). These channels are likely responsible for acute changes that might initiate other longer-term responses in the heart but are nonetheless important to consider when examining possible transducers of systemic and tissue alterations to the cardiomyocyte.

Changes in wall stress induce signaling pathways that are associated with the development of cardiac pathology. The many intracellular signaling pathways that mediate responses to increased demand on the heart have been extensively reviewed elsewhere (Force et al., 1999; Molkentin and Dorn, 2001; Heineke and Molkentin, 2006). Here, we focus on pathways that are intimately involved in pathogenesis (Fig. 4). Although their effects in compensatory responses early in pathology initially increase function by promoting growth and contractility, persistent responses eventually compromise function.

Figure 4.

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Figure 4. Signaling pathways associated with cardiac hypertrophy.

Although many pathways are associated with cardiomyopathy, up-regulation of transcription and induction of apoptosis are major mediators of pathogenic responses in the heart. The GPCR-associated pathway (dark red) can be activated by ET-1 and AngII, which are released in response to reduced contractility, and mediates contractile adaptation through increased calcium release from the sarcoplasmic reticulum. Increased intracellular calcium activates calmodulin and induces activation of the transcription factor MEF2. Incorporation into the sarcomere of mutant proteins that exhibit reduced ATP efficiency inhibits the sequestration of calcium from the cytosol and further enhances increases in intracellular calcium concentration. GPCR signaling is also associated with activation of the Akt signaling pathway (light green) that induces fetal gene expression and the cardiac hypertrophic response through inhibition of GSK3β. Apoptotic pathways (light blue) are induced by cytochrome c (CytC) release from mitochondria and activation of death receptors (like FasR) by cytokines such as TNF. Calcium overload and myocyte loss significantly contribute to reduced contractility in many forms of cardiomyopathy. ET-1, endothelin-1; HDAC, histone deacetylase; NFAT, nuclear factor of activated T cells; MEF-2, myocyte enhancer factor 2; SERCA, sarco/endoplasmic reticulum calcium-ATPase; cFLIP, cellular FLICE-inhibitory protein; AngII, angiotensin II; FasR, Fas receptor.

http://jcb.rupress.org/content/194/3/355.full

For Disruption of Calcium Homeostasis in Cardiomyocyte Cells, see

Part VI: Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-contractile/

Section Three

The Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

This topic is covered in

Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/

Summary

Justin D Pearlman, MD, PhD, FACC  PENDING

REFERENCES

Vascular Smooth Muscle Cells

References in http://jp.physoc.org/content/586/21/5047.full.pdf

Amberg GC, Navedo MF, Nieves-Cintr ´on M, Molkentin JD &

Santana LF (2007). Calcium sparklets regulate local and

global calcium in murine arterial smooth muscle. J Physiol

579, 187–201.

Aoyama M, Yamada A,Wang J, Ohya S, Furuzono S, Goto T,

Hotta S, Ito Y, Matsubara T, Shimokata K, Chen SRW,

Imaizumi Y & Nakayama S (2004). Requirement of

ryanodine receptors for pacemaker Ca2+ activity in ICC and

HEK293 cells. J Cell Sci 117, 2813–2825.

Berridge MJ (2007). Inositol trisphosphate and calcium

oscillations. Biochem Soc Symp 74, 1–7.

Berridge MJ (2008). Cell Signalling Biology. Portland Press

Limited (www.cellsignallingbiology.org).

Berridge MJ, Bootman MD & Roderick HL (2003). Calcium

signalling: Dynamics, homeostasis and remodelling. Nat Rev

Mol Cell Biol 4, 517–529.

Berridge MJ & Dupont G (1994). Spatial and temporal

signalling by calcium. Curr Opin Cell Biol 6, 267–274.

Blanks AM, Zhao Z-H, Shmygol A, Bru-Mercier G, Astle S &

Thornton S (2007). Characterization of the molecular and

electrophysiological properties of the T-type calcium

channel in human myometrium. J Physiol 581, 915–926.

Bradley KN, Currie S, MacMillan D, Muir TC & McCarron JG

(2003). Cyclic ADP-ribose inceases Ca2+ removal in smooth

muscle. J Cell Sci 116, 4291–4306.

Bradley E, HollywoodMA, Johnston L, Large RJ, Matsuda T,

Baba A, McHale NG, Thornbury KD & Sergeant GP (2006).

Contribution of reverse Na+–Ca2+ exchange to spontaneous

activity in interstitial cells of Cajal in the rabbit urethra.

J Physiol 574, 651–661.

Brain KL, Cuprian AM,Williams DJ & Cunnane TC (2003).

The sources and sequestration of Ca2+ transients in the

mouse vas deferens. J Physiol 553, 627–635.

Brain KL, Jackson MJ, Trout SJ & Cunnane TC (2002).

Intermittent ATP release from nerve terminals elicits focal

smooth muscle Ca2+ transients in mouse vas deferens.

J Physiol 541, 849–862.

Brown A, Cornwell T, Korniyenko I, Solodushko V, Bond CT,

Adelman JP & Taylor MS (2007). Myometrial expression of

small conductance Ca2+-activated K+ channels depresses

phasic uterine contractions. Am J Physiol Cell Physiol 292,

C832–C840.

Burdyga T &Wray S (2005). Action potential refractory period

in ureter smooth muscle is set by Ca sparks and BK channels.

Nature 436, 559–562.

Collier ML, Ji G,Wang Y-X & Kotlikoff MI (2000).

Calcium-induced calcium release in smooth muscle. Loose

coupling between the action potential and calcium release.

J Gen Physiol 115, 653–662.

Craven M, Sergeant GP, Hollywood MA, McHale NG &

Thornbury KD (2004). Modulation of spontaneous

Ca2+-activated Cl− currents in the rabbit corpus cavernosum

by the nitric oxide-cGMP pathway. J Physiol 556, 495–506.

Dai JM, Kuo K-H, Leo JM, van Breemen C & Lee C-H (2006).

Mechanism of ACh-induced asynchronous calcium waves

and tonic contraction in porcine tracheal muscle bundle.

Am J Physiol Lung Cell Mol Physiol 290, L459–L469.

Deshpande DA,White TA, Dogan S,Walseth TF, Panettieri RA

& Kanna MS (2005). CD38/cyclic ADP-ribose signalling: role

in the regulation of calcium homeostasis in airway smooth

muscle. Am J Physiol Lung Cell Mol Physiol 288, L733–L788.

Essin K,Welling A, Hofmann F, Luft FC, Gollasch M &

Moosmang S (2007). Indirect coupling between CaV1.2

channels and ryanodine receptors to generate Ca2+ sparks in

murine arterial smooth muscle cells. J Physiol 584, 205–219.

Haddock RE & Hill CE (2002). Differential activation of ion

channels by inositol 1,4,5-trisphosphate (IP3)- and

ryanodine-sensitive calcium stores in rat basilar artery

vasomotion. J Physiol 545, 615–627.

C2008 The Author. Journal compilation C 2008 The Physiological Society

Downloaded from J Physiol (jp.physoc.org) by guest on September 12, 2013

5060 M. J. Berridge J Physiol 586.21

Haddock RE & Hill CE (2005). Rhythmicity in arterial smooth

muscle. J Physiol 566, 645–656.

Hashitani H, Fukuta H, Takano H, Klemm MF & Suzuki H

(2001). Origin and propagation of spontaneous excitation in

smooth muscle of the guinea-pig urinary bladder. J Physiol

530, 273–286.

Hashitani H (2006). Interaction between interstitial cells and

smooth muscles in the lower urinary tract and penis.

J Physiol 576, 707–714.

Hashitani H & Brading AF (2003a). Electrical properties of

detrusor smooth muscles from the pig and human urinary

bladder. Br J Pharmacol 140, 146–158.

Hashitani H & Brading AF (2003b). Ionic basis for the

regulation of spontaneous excitation in detrusor smooth

muscle cells of the guinea-pig urinary bladder.

Br J Pharmacol 140, 159–169.

Hashitani H, Brading AF & Suzuki H (2004). Correlation

between spontaneous electrical, calcium and mechanical

activity of detrusor smooth muscle of the guinea-pig

bladder. Br J Pharmacol 141, 183–193.

Hashitani H, Bramich NJ & Hirst GDS (2000). Mechanisms of

excitatory neuromuscular transmission in the guinea-pig

urinary bladder. J Physiol 524, 565–579.

Hashitani H & Suzuki H (2007). Properties of spontaneous

Ca2+ transients recorded from interstitial cells of Cajal-like

cells of the rabbit urethra in situ. J Physiol 583, 505–519.

Hashitani H, Yanai Y, Shirasawa N, Soji T, Tomita A, Kohri K &

Suzuki H (2005). Interaction between spontaneous and

neurally mediated regulation of smooth muscle cell tone in

the rabbit corpus cavernosum. J Physiol 569, 723–735.

Heppner TJ, Bonev AD & Nelson MT (2005). Elementary

purinergic Ca2+ transients evoked by nerve stimulation in

rat urinary bladder smooth muscle. J Physiol 564, 201–212.

Hirst GDS &Ward SM (2003). Interstitial cells: involvement in

rhythmicity and neural control of gut smooth muscle.

J Physiol 550, 337–346.

Hotta S, Morimura K, Ohya S, Muraki K, Takeshima H &

Imaizumi Y (2007). Ryanodine receptor type 2 deficiency

changes excitation–contraction coupling and membrane

potential in urinary bladder smooth muscle. J Physiol 582,

489–506.

Iino M, Kasai H & Yamazawa T (1994). Visualization of neural

control of intracellular Ca2+ concentration in single vascular

smooth muscle cells in situ. EMBO J 13, 5026–5031.

Imtiaz MS, Katnik CP, Smith DW& van Helden DF (2006).

Role of voltage-dependent modulation of store Ca2+ release

in synchronization of Ca2+ oscillations. Biophys J 90, 1–23.

Imtiaz MS, Zhao J, Hosaka K, von derWeid P-Y, Crowe M &

van Helden DF (2007). Pacemaking through Ca2+ stores

interacting as coupled oscillators via membrane

depolarization. Biophys J 92, 3843–3861.

Johnstone L, Sergeant GP, Hollywood MA, Thornbury KD &

McHale NG (2005). Calcium oscillations in interstitial cells

of the rabbit urethra. J Physiol 565, 449–461.

Kim YC, Koh SD & Sanders KM (2002). Voltage-dependent

inward currents of intestinal cells of Cajal from murine colon

and small intestine. J Physiol 541, 797–810.

Kito Y & Suzuki H (2003). Properties of pacemaker potentials

recorded from myenteric interstitial cells of Cajal distributed

in the mouse small intestine. J Physiol 553, 803–818.

Kito Y,Ward SM & Sanders KM (2005). Pacemaker potentials

generated by interstitial cells of Cajal in the murine intestine.

Am J Physiol Cell Physiol 288, C710–C720.

Komuro T (2006). Structure and organization of interstitial

cells of Cajal in the gastrointestinal tract. J Physiol 576,

653–658.

Kuo K-H, Dai J, Seow CY, Lee C-H & van Breemen C (2003).

Relationship between asynchronous Ca2+ waves and force

development in intact smooth muscle bundles of the porcine

trachea. Am J Physiol Lung Cell Mol Physiol 285,

L1345–L1353.

Kupittayanant S, Luckas MJM &Wray S (2002). Effect of

inhibiting the sarcoplasmic reticulum on spontaneous and

oxytocin-induced contractions of human myometrium.

Br J Obstet Gynaec 109, 289–296.

Lamboley M, Schuster A, B´eny J-L & Meister J-J (2003).

Recruitment of smooth muscle cells and arterial vasomotion.

Am J Physiol Heart Circ Physiol 285, H562–H569.

Lamont C, Vainorius E &WierWG (2003). Purinergic and

adrenergic Ca2+ transients during neurogenic contractions

of rat mesenteric small arteries. J Physiol 549, 801–808.

Lamont C &WierWG (2002). Evoked and spontaneous

purinergic junctional Ca2+ transients (jCaTs) in rat small

arteries. Circ Res 91, 454–456.

Lang RJ, Hashitani H, Tonta MA, Parkington HC & Suzuki H

(2007). Spontaneous electrical and Ca2+ signals in typical

and atypical smooth muscle cells and interstitial cell of

Cajal-like cells of mouse renal pelvis. J Physiol 583,

1049–1068.

Lee C-H, Poburko D, Sahota P, Sandhu J, Ruehlmann DO &

van Breemen C (2001). The mechanism of

phenylephrine-mediated [Ca2+]i oscillations underlying

tonic contraction in the rabbit inferior vena cava. J Physiol

534, 641–650.

Liu X & Farley JM (1996). Acetylcholine-induced chloride

current oscillations in swine tracheal smooth muscle cells.

J Pharmacol Exp Ther 276, 178–186.

McCarron JG, MacMillan D, Bradley KN, Chalmers S & Muir

TC (2004). Origin and mechanisms of Ca2+ waves in smooth

muscle as revealed by localized photolysis of caged inositol

1,4,5-trisphosphate. J Biol Chem 279, 8417–8427.

McHale NG, Hollywood MA, Sergeant GP, Shafei M,

Thornbury KT &Ward SM (2006). Organization and

function of ICC in the urinary tract. J Physiol 576, 689–694.

Mauban JRH, Lamont C, Balke CW&WierWG (2001).

Adrenergic stimulation of rat resistance arteries affects Ca2+

sparks, Ca2+ waves, and Ca2+ oscillations. Am J Physiol Heart

Circ Physiol 280, H2399–H2405.

Meredith AL, Thorneloe KS,WernerME, Nelson MT & Aldrich

RW(2004). Overactive bladder and incontinence in the

absence of the BK large conductance Ca2+-activated K+

channel. J Biol Chem 279, 36746–36752.

Morimura K, Ohi Y, Yamamura H, Ohya S, Muraki K &

Imaizumi Y (2005). Two-step Ca2+ intracellular release

underlies excitation-contraction coupling in mouse urinary

bladder myocytes. Am J Physiol Cell Physiol 290, C388–C403.

Mulryan K, Gitterman DP, Lewis CJ, Vial C, Leckie BJ, Cobb

AL, Brown JE, Conley EC, Buell G, Pritchard CA & Evans RJ

(2000). Reduced vas deferens contraction and male

infertility in mice lacking P2X1 receptors. Nature 403, 86–89.

C2008 The Author. Journal compilation C 2008 The Physiological Society

Downloaded from J Physiol (jp.physoc.org) by guest on September 12, 2013

J Physiol 586.21 Smooth muscle cell calcium activation mechanisms 5061

Nakao K, Inoue Y, Okabe K, Kawarabayashi T & Kitamura K

(1997). Oxytocin enhances action potentials in pregnant

human myometrium – a study with microelectrodes.

Am J Obstet Gynecol 177, 222–228.

Ohi Y, Yamamura H, Nagano N, Ohya S, Muraki K,Watanabe

M & Imaizumi Y (2001). Local Ca2+ transients and

distribution of BK channels and ryanodine receptors in

smooth muscle cells of guinea-pig vas deferens and urinary

bladder. J Physiol 534, 313–326.

Park KJ, Hennig GW, Lee H-T, Spencer NJ,Ward SM, Sith TK

& Sanders KM (2006). Spatial and temporal mapping of

pacemaker activity in interstitial cells of Cajal in mouse

ileum in situ. Am J Physiol Cell Physiol 290,

C1411–C1427.

Peng H, Matchkov V, Ivarsen A, Aalkjaer C & Nilsson H

(2001). Hypothesis for the initiation of vasomotion. Circ Res

88, 810–815.

Peppiatt-Wildman CM, Albert AP, Saleh SN & LargeWA

(2007). Endothelin-1 activates a Ca2+-permeable cation

channel with TRPC3 and TRPC7 properties in rabbit

coronary artery myocytes. J Physiol 580,

755–764.

Perez JF & Sanderson MJ (2005a). The frequency of calcium

oscillations induced by 5-HT, ACH, and KCl determine the

contraction of smooth muscle cells of intrapulmonary

bronchioles. J Gen Physiol 125, 535–553.

Perez JF & Sanderson MJ (2005b). The contraction of smooth

muscle cells of intrapulmonary arterioles is determined by

the frequency of Ca2+ oscillations induced by 5-HT and KCl.

J Gen Physiol 125, 555–567.

Rebolledo A, Speroni F, Raingo J, Salemme SV, Tanzi F, Munin

V, A˜n´on MC & Milesi V (2006). The Na+/Ca2+ exchanger is

active and working in the reverse mode in human umbilical

artery smooth muscle. Biochem Biophys Res Commun 339,

840–845.

Saleh SN, Albert AP, Peppiatt-Wildman CM & LargeWA

(2008). Diverse properties of store-operated TRPC channels

activated by protein kinase C in vascular myocytes. J Physiol

586, 2463–2476.

Sanders KM, Koy SD &Ward SM (2006). Interstitial cells of

Cajal as pacemakers in the gastrointestinal tract. Annu Rev

Physiol 68, 307–343.

Sanderson MJ, Delmotte P, Bai Y & Perez-Zogbhi JF (2008).

Regulation of airway SMC contractility by Ca2+ signaling

and sensitivity. Proc Am Thorac Soc 5, 23–31.

Sergeant GP, Hollywood MA, McCloskey KD, Thornbury KD

& McHale NG (2000). Specialised pacemaking cells in the

rabbit urethra. J Physiol 526, 359–366.

Sergeant GP, Hollywood MA, McHale NG & Thornbury KD

(2006a). Ca2+ signalling in urethral interstitial cells of Cajal.

J Physiol 576, 715–720.

Sergeant GP, Johnston L, McHale NG, Thornbury KD &

Hollywood MA (2006b). Activation of the cGMP/PKG

pathway inhibits electrical activity in rabbit urethral

interstitial cells of Cajal by reducing the spatial spread of

Ca2+ waves. J Physiol 574, 167–181.

Shaw L, O’Neill S, Jones CJP, Austin C & Taggart MJ (2004).

Comparison of U46619-, endothelin-1- or

phenylephrine-induced changes in cellular Ca2+ profiles and

Ca2+ sensitization of constriction of pressurised rat

resistance arteries. Br J Pharm 141, 678–688.

Shmygol A, Blanks AM, Bru-Mercier G, Gullam JE & Thornton

S (2007). Control of uterine Ca2+ by membrane voltage:

Toward understanding the excitation-contraction coupling

in human myometrium. Ann N Y Acad Sci 1101, 97–109.

Somlyo AP & Somlyo AV (2003). Ca2+ sensitivity of smooth

muscle and nonmuscle myosin II: modulated by G proteins,

kinases, and myosin phosphatase. Physiol Rev 83, 1325–1358.

van Helden DF & Imtiaz MS (2003). Ca2+ phase waves: a basis

for cellular pacemaking and long-range synchronicity in the

guinea-pig gastric pylorus. J Physiol 548, 271–296.

Wang H, Eto M, SteersWD, Somlyo AP & Somlyo AV (2002).

RhoA-mediated Ca2+ sensitization in erectile function. J Biol

Chem 277, 30614–30621.

Ward SM & Sanders KM (2006). Involvement of intramuscular

interstitial cells of Cajal in neuroeffector transmission in the

gastrointestinal tract. J Physiol 576, 675–682.

White C & McGeown JG (2003). Inositol 1,4,5-trisphosphate

receptors modulate Ca2+ sparks and Ca2+ store content in

vas deferens myocytes. Am J Physiol Cell Physiol 285,

C195–C204.

Wray S (2007). Insights into the uterus. Exp Physiol 92,

621–631.

Wray S, Burdyga T & Noble K (2005). Calcium signalling in

smooth muscle. Cell Calcium 38, 397–407.

Wray S & Noble K (2008). Sex hormones and excitationcontraction

coupling in the uterus: The effects of oestrus and

hormones. J Neuroendocrinol 20, 451–461.

Wray S & Shmygol A (2007). Role of the calcium store in

uterine contractility. Semin Cell Dev Biol 18, 315–320.

Yamazawa T & Iino M (2002). Simultaneous imaging of Ca2+

signals in interstitial cells of Cajal and longitudinal smooth

muscle cells during rhythmic activity in mouse ileum.

J Physiol 538, 823–835.

Young RC (2007). Myocytes, myometrium, and uterine

contraction. Ann N Y Acad Sci 1101, 72–84.

C2008 The Author. Journal compilation C 2008 The Physiological Society

Downloaded from JCB

Cardiomyocytes Cells

References in http://jcb.rupress.org/content/194/3/355.full

.         ↵ Adams, J.W., D.S. Migita, M.K. Yu, R. Young, M.S. Hellickson, F.E. Castro-Vargas, J.D. Domingo, P.H. Lee, J.S. Bui, S.A. Henderson. 1996. Prostaglandin F2 alpha stimulates hypertrophic growth of cultured neonatal rat ventricular myocytes. J. Biol. Chem. 271:1179–1186. doi:10.1074/jbc.271.2.1179 Abstract/FREE Full Text

.         ↵ Akyürek, O., N. Akyürek, T. Sayin, I. Dinçer, B. Berkalp, G. Akyol, M. Ozenci, D. Oral. 2001. Association between the severity of heart failure and the susceptibility of myocytes to apoptosis in patients with idiopathic dilated cardiomyopathy. Int. J. Cardiol. 80:29–36. doi:10.1016/S0167-5273(01)00451-X CrossRefMedline

.         ↵ Ashrafian, H., M.P. Frenneaux. 2007. Metabolic modulation in heart failure: the coming of age. Cardiovasc. Drugs Ther. 21:5–7. doi:10.1007/s10557-007-6000-z CrossRefMedline

.         ↵ Basso, C., D. Corrado, F.I. Marcus, A. Nava, G. Thiene. 2009. Arrhythmogenic right ventricular cardiomyopathy. Lancet. 373:1289–1300. doi:10.1016/S0140-6736(09)60256-7 CrossRefMedline

.         ↵ Berko, B.A., M. Swift. 1987. X-linked dilated cardiomyopathy. N. Engl. J. Med. 316:1186–1191. doi:10.1056/NEJM198705073161904 Medline

.         ↵ Buvoli, M., M. Hamady, L.A. Leinwand, R. Knight. 2008. Bioinformatics assessment of beta-myosin mutations reveals myosin’s high sensitivity to mutations. Trends Cardiovasc. Med. 18:141–149. doi:10.1016/j.tcm.2008.04.001 CrossRefMedline

.         ↵ Bybee, K.A., T. Kara, A. Prasad, A. Lerman, G.W. Barsness, R.S. Wright, C.S. Rihal. 2004. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Ann. Intern. Med. 141:858–865. Abstract/FREE Full Text

.         ↵ Chin, T.K., J.K. Perloff, R.G. Williams, K. Jue, R. Mohrmann. 1990. Isolated noncompaction of left ventricular myocardium. A study of eight cases. Circulation. 82:507–513. doi:10.1161/01.CIR.82.2.507 Abstract/FREE Full Text

.         ↵ Communal, C., K. Singh, D.R. Pimentel, W.S. Colucci. 1998. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway. Circulation. 98:1329–1334. Abstract/FREE Full Text

.         ↵ Corrado, D., C. Basso, G. Thiene, W.J. McKenna, M.J. Davies, F. Fontaliran, A. Nava, F. Silvestri, C. Blomstrom-Lundqvist, E.K. Wlodarska, et al. 1997. Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study. J. Am. Coll. Cardiol. 30:1512–1520. doi:10.1016/S0735-1097(97)00332-X Abstract

.         ↵ Cregler, L.L. 1989. Progression from hypertrophic cardiomyopathy to dilated cardiomyopathy. J. Natl. Med. Assoc. 81:820: 824–826. Search Google Scholar

.         ↵ D’Angelo, D.D., Y. Sakata, J.N. Lorenz, G.P. Boivin, R.A. Walsh, S.B. Liggett, G.W. Dorn II. 1997. Transgenic Galphaq overexpression induces cardiac contractile failure in mice. Proc. Natl. Acad. Sci. USA. 94:8121–8126. doi:10.1073/pnas.94.15.8121 Abstract/FREE Full Text

.         ↵ Dávila-Román, V.G., G. Vedala, P. Herrero, L. de las Fuentes, J.G. Rogers, D.P. Kelly, R.J. Gropler. 2002. Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J. Am. Coll. Cardiol. 40:271–277. doi:10.1016/S0735-1097(02)01967-8 Abstract/FREE Full Text

.         ↵ Davis, J., H. Wen, T. Edwards, J.M. Metzger. 2007. Thin filament disinhibition by restrictive cardiomyopathy mutant R193H troponin I induces Ca2+-independent mechanical tone and acute myocyte remodeling. Circ. Res. 100:1494–1502. doi:10.1161/01.RES.0000268412.34364.50 Abstract/FREE Full Text

.         ↵ de Jonge, H.W., D.H. Dekkers, B.C. Tilly, J.M. Lamers. 2002. Cyclic stretch and endothelin-1 mediated activation of chloride channels in cultured neonatal rat ventricular myocytes. Clin. Sci. 103(Suppl 48):148S–151S. Medline

.         ↵ Deinum, J., J.M. van Gool, M.J. Kofflard, F.J. ten Cate, A.H. Danser. 2001. Angiotensin II type 2 receptors and cardiac hypertrophy in women with hypertrophic cardiomyopathy. Hypertension. 38:1278–1281. doi:10.1161/hy1101.096114 Abstract/FREE Full Text

.         ↵ Dobrin, J.S., D. Lebeche. 2010. Diabetic cardiomyopathy: signaling defects and therapeutic approaches. Expert Rev. Cardiovasc. Ther. 8:373–391. doi:10.1586/erc.10.17 CrossRefMedline

.         ↵ Dolci, A., R. Dominici, D. Cardinale, M.T. Sandri, M. Panteghini. 2008. Biochemical markers for prediction of chemotherapy-induced cardiotoxicity: systematic review of the literature and recommendations for use. Am. J. Clin. Pathol. 130:688–695. doi:10.1309/AJCPB66LRIIVMQDR Abstract/FREE Full Text

.         ↵ Edwards, B.S., R.S. Zimmerman, T.R. Schwab, D.M. Heublein, J.C. Burnett Jr. 1988. Atrial stretch, not pressure, is the principal determinant controlling the acute release of atrial natriuretic factor. Circ. Res. 62:191–195. Abstract/FREE Full Text

.         ↵ Esposito, G., S.V. Prasad, A. Rapacciuolo, L. Mao, W.J. Koch, H.A. Rockman. 2001. Cardiac overexpression of a G(q) inhibitor blocks induction of extracellular signal-regulated kinase and c-Jun NH(2)-terminal kinase activity in in vivo pressure overload. Circulation. 103:1453–1458. Abstract/FREE Full Text

.         ↵ Flavigny, J., M. Souchet, P. Sébillon, I. Berrebi-Bertrand, B. Hainque, A. Mallet, A. Bril, K. Schwartz, L. Carrier. 1999. COOH-terminal truncated cardiac myosin-binding protein C mutants resulting from familial hypertrophic cardiomyopathy mutations exhibit altered expression and/or incorporation in fetal rat cardiomyocytes. J. Mol. Biol. 294:443–456. doi:10.1006/jmbi.1999.3276 CrossRefMedline

.         ↵ Force, T., R. Hajjar, F. Del Monte, A. Rosenzweig, G. Choukroun. 1999. Signaling pathways mediating the response to hypertrophic stress in the heart. Gene Expr. 7:337–348. Medline

.         ↵ Freedom, R.M., S.J. Yoo, D. Perrin, G. Taylor, S. Petersen, R.H. Anderson. 2005. The morphological spectrum of ventricular noncompaction. Cardiol. Young. 15:345–364. doi:10.1017/S1047951105000752 CrossRefMedline

.         ↵ Frey, N., E.N. Olson. 2003. Cardiac hypertrophy: the good, the bad, and the ugly. Annu. Rev. Physiol. 65:45–79. doi:10.1146/annurev.physiol.65.092101.142243 CrossRefMedline

.         ↵ Geng, Y.J., Y. Ishikawa, D.E. Vatner, T.E. Wagner, S.P. Bishop, S.F. Vatner, C.J. Homcy. 1999. Apoptosis of cardiac myocytes in Gsalpha transgenic mice. Circ. Res. 84:34–42. Abstract/FREE Full Text

.         ↵ Gill, C., R. Mestril, A. Samali. 2002. Losing heart: the role of apoptosis in heart disease—a novel therapeutic target? FASEB J. 16:135–146. doi:10.1096/fj.01-0629com Abstract/FREE Full Text

.         ↵ Grogan, M., M.M. Redfield, K.R. Bailey, G.S. Reeder, B.J. Gersh, W.D. Edwards, R.J. Rodeheffer. 1995. Long-term outcome of patients with biopsy-proved myocarditis: comparison with idiopathic dilated cardiomyopathy. J. Am. Coll. Cardiol. 26:80–84. doi:10.1016/0735-1097(95)00148-S Abstract

.         ↵ Gupta, A., N.S. Aberle II, J. Ren, A.C. Sharma. 2005. Endothelin-converting enzyme-1-mediated signaling in adult rat ventricular myocyte contractility and apoptosis during sepsis. J. Mol. Cell. Cardiol. 38:527–537. doi:10.1016/j.yjmcc.2005.01.002 CrossRefMedline

.         ↵ Haq, S., G. Choukroun, Z.B. Kang, H. Ranu, T. Matsui, A. Rosenzweig, J.D. Molkentin, A. Alessandrini, J. Woodgett, R. Hajjar, et al. 2000. Glycogen synthase kinase-3beta is a negative regulator of cardiomyocyte hypertrophy. J. Cell Biol. 151:117–130. doi:10.1083/jcb.151.1.117 Abstract/FREE Full Text

.         ↵ Heineke, J., J.D. Molkentin. 2006. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat. Rev. Mol. Cell Biol. 7:589–600. doi:10.1038/nrm1983 CrossRefMedline

.         ↵ Herron, T.J., K.S. McDonald. 2002. Small amounts of alpha-myosin heavy chain isoform expression significantly increase power output of rat cardiac myocyte fragments. Circ. Res. 90:1150–1152. doi:10.1161/01.RES.0000022879.57270.11 Abstract/FREE Full Text

.         ↵ Herron, T.J., R. Vandenboom, E. Fomicheva, L. Mundada, T. Edwards, J.M. Metzger. 2007. Calcium-independent negative inotropy by beta-myosin heavy chain gene transfer in cardiac myocytes. Circ. Res. 100:1182–1190. doi:10.1161/01.RES.0000264102.00706.4e Abstract/FREE Full Text

.         ↵ Hoogerwaard, E.M., P.A. van der Wouw, A.A. Wilde, E. Bakker, P.F. Ippel, J.C. Oosterwijk, D.F. Majoor-Krakauer, A.J. van Essen, N.J. Leschot, M. de Visser. 1999. Cardiac involvement in carriers of Duchenne and Becker muscular dystrophy. Neuromuscul. Disord. 9:347–351. doi:10.1016/S0960-8966(99)00018-8 CrossRefMedline

.         ↵ Huang, X.P., J.F. Du. 2004. Troponin I, cardiac diastolic dysfunction and restrictive cardiomyopathy. Acta Pharmacol. Sin. 25:1569–1575. Medline

.         ↵ Huang, Y., R.P. Hickey, J.L. Yeh, D. Liu, A. Dadak, L.H. Young, R.S. Johnson, F.J. Giordano. 2004. Cardiac myocyte-specific HIF-1alpha deletion alters vascularization, energy availability, calcium flux, and contractility in the normoxic heart. FASEB J. 18:1138–1140. doi:10.1096/fj.03-1377com Abstract/FREE Full Text

.         ↵ Iacovoni, A., R. De Maria, A. Gavazzi. 2010. Alcoholic cardiomyopathy. J. Cardiovasc. Med. (Hagerstown). 11:884–892. doi:10.2459/JCM.0b013e32833833a3 CrossRefMedline

.         ↵ Ingwall, J.S., R.G. Weiss. 2004. Is the failing heart energy starved? On using chemical energy to support cardiac function. Circ. Res. 95:135–145. doi:10.1161/01.RES.0000137170.41939.d9 Abstract/FREE Full Text

.         ↵ Iwai-Kanai, E., K. Hasegawa, M. Araki, T. Kakita, T. Morimoto, S. Sasayama. 1999. alpha- and beta-adrenergic pathways differentially regulate cell type-specific apoptosis in rat cardiac myocytes. Circulation. 100:305–311. Abstract/FREE Full Text

.         ↵ Kalsi, K.K., R.T. Smolenski, R.D. Pritchard, A. Khaghani, A.M. Seymour, M.H. Yacoub. 1999. Energetics and function of the failing human heart with dilated or hypertrophic cardiomyopathy. Eur. J. Clin. Invest. 29:469–477. doi:10.1046/j.1365-2362.1999.00468.x CrossRefMedline

.         ↵ Kamisago, M., S.D. Sharma, S.R. DePalma, S. Solomon, P. Sharma, B. McDonough, L. Smoot, M.P. Mullen, P.K. Woolf, E.D. Wigle, et al. 2000. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N. Engl. J. Med. 343:1688–1696. doi:10.1056/NEJM200012073432304 CrossRefMedline

.         ↵ Kaneda, T., C. Naruse, A. Kawashima, N. Fujino, T. Oshima, M. Namura, S. Nunoda, S. Mori, T. Konno, H. Ino, et al. 2008. A novel beta-myosin heavy chain gene mutation, p.Met531Arg, identified in isolated left ventricular non-compaction in humans, results in left ventricular hypertrophy that progresses to dilation in a mouse model. Clin. Sci. 114:431–440. doi:10.1042/CS20070179 CrossRefMedline

.         ↵ Kantor, P.F., M.A. Robertson, J.Y. Coe, G.D. Lopaschuk. 1999. Volume overload hypertrophy of the newborn heart slows the maturation of enzymes involved in the regulation of fatty acid metabolism. J. Am. Coll. Cardiol. 33:1724–1734. doi:10.1016/S0735-1097(99)00063-7 Abstract/FREE Full Text

.         ↵ Karam, S., M.J. Raboisson, C. Ducreux, L. Chalabreysse, G. Millat, A. Bozio, P. Bouvagnet. 2008. A de novo mutation of the beta cardiac myosin heavy chain gene in an infantile restrictive cardiomyopathy. Congenit. Heart Dis. 3:138–143. doi:10.1111/j.1747-0803.2008.00165.x CrossRefMedline

.         ↵ Katritsis, D., P.T. Wilmshurst, J.A. Wendon, M.J. Davies, M.M. Webb-Peploe. 1991. Primary restrictive cardiomyopathy: clinical and pathologic characteristics. J. Am. Coll. Cardiol. 18:1230–1235. doi:10.1016/0735-1097(91)90540-P Abstract

.         ↵ Keeling, P.J., Y. Gang, G. Smith, H. Seo, S.E. Bent, V. Murday, A.L. Caforio, W.J. McKenna. 1995. Familial dilated cardiomyopathy in the United Kingdom. Br. Heart J. 73:417–421. doi:10.1136/hrt.73.5.417 Abstract/FREE Full Text

.         ↵ Kinnunen, P., O. Vuolteenaho, H. Ruskoaho. 1993. Mechanisms of atrial and brain natriuretic peptide release from rat ventricular myocardium: effect of stretching. Endocrinology. 132:1961–1970. doi:10.1210/en.132.5.1961 Abstract/FREE Full Text

.         ↵ Knowlton, K.U., M.C. Michel, M. Itani, H.E. Shubeita, K. Ishihara, J.H. Brown, K.R. Chien. 1993. The alpha 1A-adrenergic receptor subtype mediates biochemical, molecular, and morphologic features of cultured myocardial cell hypertrophy. J. Biol. Chem. 268:15374–15380. Abstract/FREE Full Text

.         ↵ Kojima, M., I. Shiojima, T. Yamazaki, I. Komuro, Z. Zou, Y. Wang, T. Mizuno, K. Ueki, K. Tobe, T. Kadowaki, et al. 1994. Angiotensin II receptor antagonist TCV-116 induces regression of hypertensive left ventricular hypertrophy in vivo and inhibits the intracellular signaling pathway of stretch-mediated cardiomyocyte hypertrophy in vitro. Circulation. 89:2204–2211. Abstract/FREE Full Text

.         ↵ Krown, K.A., M.T. Page, C. Nguyen, D. Zechner, V. Gutierrez, K.L. Comstock, C.C. Glembotski, P.J. Quintana, R.A. Sabbadini. 1996. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death. J. Clin. Invest. 98:2854–2865. doi:10.1172/JCI119114 Medline

.         ↵ Kuwahara, K., Y. Saito, M. Takano, Y. Arai, S. Yasuno, Y. Nakagawa, N. Takahashi, Y. Adachi, G. Takemura, M. Horie, et al. 2003. NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function. EMBO J. 22:6310–6321. doi:10.1093/emboj/cdg601 CrossRefMedline

.         ↵ Le Guennec, J.Y., N. Peineau, J.A. Argibay, K.G. Mongo, D. Garnier. 1990. A new method of attachment of isolated mammalian ventricular myocytes for tension recording: length dependence of passive and active tension. J. Mol. Cell. Cardiol. 22:1083–1093. doi:10.1016/0022-2828(90)90072-A CrossRefMedline

.         ↵ Lopaschuk, G.D., M.A. Spafford, D.R. Marsh. 1991. Glycolysis is predominant source of myocardial ATP production immediately after birth. Am. J. Physiol. 261:H1698–H1705. Medline

.         ↵ Lowes, B.D., W. Minobe, W.T. Abraham, M.N. Rizeq, T.J. Bohlmeyer, R.A. Quaife, R.L. Roden, D.L. Dutcher, A.D. Robertson, N.F. Voelkel, et al. 1997. Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium. J. Clin. Invest. 100:2315–2324. doi:10.1172/JCI119770 Medline

.         ↵ Luckey, S.W., L.A. Walker, T. Smyth, J. Mansoori, A. Messmer-Kratzsch, A. Rosenzweig, E.N. Olson, L.A. Leinwand. 2009. The role of Akt/GSK-3beta signaling in familial hypertrophic cardiomyopathy. J. Mol. Cell. Cardiol. 46:739–747. doi:10.1016/j.yjmcc.2009.02.010 CrossRefMedline

.         ↵ Maass, A.H., M. Buvoli. 2007. Cardiomyocyte preparation, culture, and gene transfer. Methods Mol. Biol. 366:321–330. doi:10.1007/978-1-59745-030-0_18 CrossRefMedline

.         ↵ Marian, A.J. 2000. Pathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy. Lancet. 355:58–60. doi:10.1016/S0140-6736(99)06187-5 CrossRefMedline

.         ↵ Maron, B.J., A. Pelliccia. 2006. The heart of trained athletes: cardiac remodeling and the risks of sports, including sudden death. Circulation. 114:1633–1644. doi:10.1161/CIRCULATIONAHA.106.613562 FREE Full Text

.         ↵ Maron, B.J., P.F. Nichols III, L.W. Pickle, Y.E. Wesley, J.J. Mulvihill. 1984. Patterns of inheritance in hypertrophic cardiomyopathy: assessment by M-mode and two-dimensional echocardiography. Am. J. Cardiol. 53:1087–1094. doi:10.1016/0002-9149(84)90643-X CrossRefMedline

.         ↵ Maron, B.J., J.M. Gardin, J.M. Flack, S.S. Gidding, T.T. Kurosaki, D.E. Bild. 1995. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation. 92:785–789. Abstract/FREE Full Text

.         ↵ Matsui, T., L. Li, J.C. Wu, S.A. Cook, T. Nagoshi, M.H. Picard, R. Liao, A. Rosenzweig. 2002. Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J. Biol. Chem. 277:22896–22901. doi:10.1074/jbc.M200347200 Abstract/FREE Full Text

.         ↵ Menon, S.C., B.W. Eidem, J.A. Dearani, S.R. Ommen, M.J. Ackerman, D. Miller. 2009. Diastolic dysfunction and its histopathological correlation in obstructive hypertrophic cardiomyopathy in children and adolescents. J. Am. Soc. Echocardiogr. 22:1327–1334. doi:10.1016/j.echo.2009.08.014 CrossRefMedline

.         ↵ Mestroni, L., C. Rocco, D. Gregori, G. Sinagra, A. Di Lenarda, S. Miocic, M. Vatta, B. Pinamonti, F. Muntoni, A.L. Caforio, et al.; Heart Muscle Disease Study Group. 1999. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. J. Am. Coll. Cardiol. 34:181–190. doi:10.1016/S0735-1097(99)00172-2 Abstract/FREE Full Text

.         ↵ Michael, A., S. Haq, X. Chen, E. Hsich, L. Cui, B. Walters, Z. Shao, K. Bhattacharya, H. Kilter, G. Huggins, et al. 2004. Glycogen synthase kinase-3beta regulates growth, calcium homeostasis, and diastolic function in the heart. J. Biol. Chem. 279:21383–21393. doi:10.1074/jbc.M401413200 Abstract/FREE Full Text

.         ↵ Michels, V.V., P.P. Moll, F.A. Miller, A.J. Tajik, J.S. Chu, D.J. Driscoll, J.C. Burnett, R.J. Rodeheffer, J.H. Chesebro, H.D. Tazelaar. 1992. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N. Engl. J. Med. 326:77–82. doi:10.1056/NEJM199201093260201 Medline

.         ↵ Minamisawa, S., M. Hoshijima, G. Chu, C.A. Ward, K. Frank, Y. Gu, M.E. Martone, Y. Wang, J. Ross Jr, E.G. Kranias, et al. 1999. Chronic phospholamban-sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy. Cell. 99:313–322. doi:10.1016/S0092-8674(00)81662-1 CrossRefMedline

.         ↵ Miyata, S., W. Minobe, M.R. Bristow, L.A. Leinwand. 2000. Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ. Res. 86:386–390. Abstract/FREE Full Text

.         ↵ Mogensen, J., T. Kubo, M. Duque, W. Uribe, A. Shaw, R. Murphy, J.R. Gimeno, P. Elliott, W.J. McKenna. 2003. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J. Clin. Invest. 111:209–216. CrossRefMedline

.         ↵ Molkentin, J.D., G.W. Dorn II. 2001. Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Annu. Rev. Physiol. 63:391–426. doi:10.1146/annurev.physiol.63.1.391 CrossRefMedline

.         ↵ Molkentin, J.D., J.R. Lu, C.L. Antos, B. Markham, J. Richardson, J. Robbins, S.R. Grant, E.N. Olson. 1998. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 93:215–228. doi:10.1016/S0092-8674(00)81573-1 CrossRefMedline

.         ↵ Nagata, K., R. Liao, F.R. Eberli, N. Satoh, B. Chevalier, C.S. Apstein, T.M. Suter. 1998. Early changes in excitation-contraction coupling: transition from compensated hypertrophy to failure in Dahl salt-sensitive rat myocytes. Cardiovasc. Res. 37:467–477. doi:10.1016/S0008-6363(97)00278-2 Abstract/FREE Full Text

.         ↵ Narula, J., N. Haider, R. Virmani, T.G. DiSalvo, F.D. Kolodgie, R.J. Hajjar, U. Schmidt, M.J. Semigran, G.W. Dec, B.A. Khaw. 1996. Apoptosis in myocytes in end-stage heart failure. N. Engl. J. Med. 335:1182–1189. doi:10.1056/NEJM199610173351603 CrossRefMedline

.         ↵ Narula, J., P. Pandey, E. Arbustini, N. Haider, N. Narula, F.D. Kolodgie, B. Dal Bello, M.J. Semigran, A. Bielsa-Masdeu, G.W. Dec, et al. 1999. Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy. Proc. Natl. Acad. Sci. USA. 96:8144–8149. doi:10.1073/pnas.96.14.8144 Abstract/FREE Full Text

.         ↵ Neubauer, S. 2007. The failing heart—an engine out of fuel. N. Engl. J. Med. 356:1140–1151. doi:10.1056/NEJMra063052 CrossRefMedline

.         ↵ O’Neill, B.T., E.D. Abel. 2005. Akt1 in the cardiovascular system: friend or foe? J. Clin. Invest. 115:2059–2064. doi:10.1172/JCI25900 CrossRefMedline

.         ↵ Ohler, A., J. Weisser-Thomas, V. Piacentino, S.R. Houser, G.F. Tomaselli, B. O’Rourke. 2009. Two-photon laser scanning microscopy of the transverse-axial tubule system in ventricular cardiomyocytes from failing and non-failing human hearts. Cardiol. Res. Pract. 2009:802373. Medline

.         ↵ Olivetti, G., R. Abbi, F. Quaini, J. Kajstura, W. Cheng, J.A. Nitahara, E. Quaini, C. Di Loreto, C.A. Beltrami, S. Krajewski, et al. 1997. Apoptosis in the failing human heart. N. Engl. J. Med. 336:1131–1141. doi:10.1056/NEJM199704173361603 CrossRefMedline

.         ↵ Palmiter, K.A., M.J. Tyska, D.E. Dupuis, N.R. Alpert, D.M. Warshaw. 1999. Kinetic differences at the single molecule level account for the functional diversity of rabbit cardiac myosin isoforms. J. Physiol. 519:669–678. doi:10.1111/j.1469-7793.1999.0669n.x Abstract/FREE Full Text

.         ↵ Parvatiyar, M.S., J.R. Pinto, D. Dweck, J.D. Potter. 2010. Cardiac troponin mutations and restrictive cardiomyopathy. J. Biomed. Biotechnol. 2010:350706. doi:10.1155/2010/350706 Medline

.         ↵ Peddy, S.B., L.A. Vricella, J.E. Crosson, G.L. Oswald, R.D. Cohn, D.E. Cameron, D. Valle, B.L. Loeys. 2006. Infantile restrictive cardiomyopathy resulting from a mutation in the cardiac troponin T gene. Pediatrics. 117:1830–1833. doi:10.1542/peds.2005-2301 Abstract/FREE Full Text

.         ↵ Ritter, M., E. Oechslin, G. Sütsch, C. Attenhofer, J. Schneider, R. Jenni. 1997. Isolated noncompaction of the myocardium in adults. Mayo Clin. Proc. 72:26–31. doi:10.4065/72.1.26 Abstract/FREE Full Text

.         ↵ Ro, A., W.H. Frishman. 2006. Peripartum cardiomyopathy. Cardiol. Rev. 14:35–42. doi:10.1097/01.crd.0000174805.68081.f7 CrossRefMedline

.         ↵ Rodeheffer, R.J., I. Tanaka, T. Imada, A.S. Hollister, D. Robertson, T. Inagami. 1986. Atrial pressure and secretion of atrial natriuretic factor into the human central circulation. J. Am. Coll. Cardiol. 8:18–26. doi:10.1016/S0735-1097(86)80086-9 Abstract

.         ↵ Rose, E.A., A.C. Gelijns, A.J. Moskowitz, D.F. Heitjan, L.W. Stevenson, W. Dembitsky, J.W. Long, D.D. Ascheim, A.R. Tierney, R.G. Levitan, et al.; Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. 2001. Long-term use of a left ventricular assist device for end-stage heart failure. N. Engl. J. Med. 345:1435–1443. doi:10.1056/NEJMoa012175 CrossRefMedline

.         ↵ Sack, M.N., T.A. Rader, S. Park, J. Bastin, S.A. McCune, D.P. Kelly. 1996. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation. 94:2837–2842. Abstract/FREE Full Text

.         ↵ Sadoshima, J., S. Izumo. 1993. Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism. EMBO J. 12:1681–1692. Medline

.         ↵ Sakata, Y., B.D. Hoit, S.B. Liggett, R.A. Walsh, G.W. Dorn II. 1998. Decompensation of pressure-overload hypertrophy in G alpha q-overexpressing mice. Circulation. 97:1488–1495. Abstract/FREE Full Text

.         ↵ Sasse-Klaassen, S., B. Gerull, E. Oechslin, R. Jenni, L. Thierfelder. 2003. Isolated noncompaction of the left ventricular myocardium in the adult is an autosomal dominant disorder in the majority of patients. Am. J. Med. Genet. A. 119A:162–167. doi:10.1002/ajmg.a.20075 Medline

.         ↵ Schram, K., S. De Girolamo, S. Madani, D. Munoz, F. Thong, G. Sweeney. 2010. Leptin regulates MMP-2, TIMP-1 and collagen synthesis via p38 MAPK in HL-1 murine cardiomyocytes. Cell. Mol. Biol. Lett. 15:551–563. doi:10.2478/s11658-010-0027-z CrossRefMedline

.         ↵ Schwartz, K., Y. Lecarpentier, J.L. Martin, A.M. Lompré, J.J. Mercadier, B. Swynghedauw. 1981. Myosin isoenzymic distribution correlates with speed of myocardial contraction. J. Mol. Cell. Cardiol. 13:1071–1075. doi:10.1016/0022-2828(81)90297-2 CrossRefMedline

.         ↵ Seidman, J.G., C. Seidman. 2001. The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell. 104:557–567. doi:10.1016/S0092-8674(01)00242-2 CrossRefMedline

.         ↵ Semsarian, C., M.J. Healey, D. Fatkin, M. Giewat, C. Duffy, C.E. Seidman, J.G. Seidman. 2001. A polymorphic modifier gene alters the hypertrophic response in a murine model of familial hypertrophic cardiomyopathy. J. Mol. Cell. Cardiol. 33:2055–2060. doi:10.1006/jmcc.2001.1466 CrossRefMedline

.         ↵ Shen, W.K., W.D. Edwards, S.C. Hammill, K.R. Bailey, D.J. Ballard, B.J. Gersh. 1995. Sudden unexpected nontraumatic death in 54 young adults: a 30-year population-based study. Am. J. Cardiol. 76:148–152. doi:10.1016/S0002-9149(99)80047-2 CrossRefMedline

.         ↵ Shiojima, I., K. Sato, Y. Izumiya, S. Schiekofer, M. Ito, R. Liao, W.S. Colucci, K. Walsh. 2005. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J. Clin. Invest. 115:2108–2118. doi:10.1172/JCI24682 CrossRefMedline

.         ↵ Silberbach, M., T. Gorenc, R.E. Hershberger, P.J. Stork, P.S. Steyger, C.T. Roberts Jr. 1999. Extracellular signal-regulated protein kinase activation is required for the anti-hypertrophic effect of atrial natriuretic factor in neonatal rat ventricular myocytes. J. Biol. Chem. 274:24858–24864. doi:10.1074/jbc.274.35.24858 Abstract/FREE Full Text

.         ↵ Simpson, P., A. McGrath, S. Savion. 1982. Myocyte hypertrophy in neonatal rat heart cultures and its regulation by serum and by catecholamines. Circ. Res. 51:787–801. Abstract/FREE Full Text

.         ↵ Smith, C.S., P.A. Bottomley, S.P. Schulman, G. Gerstenblith, R.G. Weiss. 2006. Altered creatine kinase adenosine triphosphate kinetics in failing hypertrophied human myocardium. Circulation. 114:1151–1158. doi:10.1161/CIRCULATIONAHA.106.613646 Abstract/FREE Full Text

.         ↵ Stanley, W.C., G.D. Lopaschuk, J.G. McCormack. 1997. Regulation of energy substrate metabolism in the diabetic heart. Cardiovasc. Res. 34:25–33. doi:10.1016/S0008-6363(97)00047-3 FREE Full Text

.         ↵ Stauffer, B.L., J.P. Konhilas, E.D. Luczak, L.A. Leinwand. 2006. Soy diet worsens heart disease in mice. J. Clin. Invest. 116:209–216. doi:10.1172/JCI24676 CrossRefMedline

.         ↵ Taigen, T., L.J. De Windt, H.W. Lim, J.D. Molkentin. 2000. Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy. Proc. Natl. Acad. Sci. USA. 97:1196–1201. doi:10.1073/pnas.97.3.1196 Abstract/FREE Full Text

.         ↵ Teekakirikul, P., S. Eminaga, O. Toka, R. Alcalai, L. Wang, H. Wakimoto, M. Nayor, T. Konno, J.M. Gorham, C.M. Wolf, et al. 2010. Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β. J. Clin. Invest. 120:3520–3529. doi:10.1172/JCI42028 CrossRefMedline

.         ↵ Torre-Amione, G., S. Kapadia, J. Lee, J.B. Durand, R.D. Bies, J.B. Young, D.L. Mann. 1996. Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation. 93:704–711. Abstract/FREE Full Text

.         ↵ Vikstrom, K.L., S.M. Factor, L.A. Leinwand. 1996. Mice expressing mutant myosin heavy chains are a model for familial hypertrophic cardiomyopathy. Mol. Med. 2:556–567. Medline

.         ↵ Wang, L., J.G. Seidman, C.E. Seidman. 2010. Narrative review: harnessing molecular genetics for the diagnosis and management of hypertrophic cardiomyopathy. Ann. Intern. Med. 152:513–520: W181. Abstract/FREE Full Text

.         ↵ Weiford, B.C., V.D. Subbarao, K.M. Mulhern. 2004. Noncompaction of the ventricular myocardium. Circulation. 109:2965–2971. doi:10.1161/01.CIR.0000132478.60674.D0 FREE Full Text

.         ↵ Yamaji, K., S. Fujimoto, Y. Ikeda, K. Masuda, S. Nakamura, Y. Saito, C. Yutani. 2005. Apoptotic myocardial cell death in the setting of arrhythmogenic right ventricular cardiomyopathy. Acta Cardiol. 60:465–470. doi:10.2143/AC.60.5.2004965 CrossRefMedline

.         ↵ Yang, Z., N.E. Bowles, S.E. Scherer, M.D. Taylor, D.L. Kearney, S. Ge, V.V. Nadvoretskiy, G. DeFreitas, B. Carabello, L.I. Brandon, et al. 2006. Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ. Res. 99:646–655. doi:10.1161/01.RES.0000241482.19382.c6 Abstract/FREE Full Text

.         ↵ Yousef, Z.R., P.W. Foley, K. Khadjooi, S. Chalil, H. Sandman, N.U. Mohammed, F. Leyva. 2009. Left ventricular non-compaction: clinical features and cardiovascular magnetic resonance imaging. BMC Cardiovasc. Disord. 9:37. doi:10.1186/1471-2261-9-37 CrossRefMedline

         .         ↵ Zhang, Y.H., J.B. Youm, H.K. Sung, S.H. Lee, S.Y. Ryu, W.K. Ho, Y.E. Earm. 2000. Stretch-activated and background non-selective cation channels in rat atrial myocytes. J. Physiol. 523:607–619. doi:10.1111/j.1469-7793.2000.00607.x Abstract/FREE Full Text

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Cardiac Ca2+ Signaling: Transcriptional Control

Posted in Biological Networks, Cardiovascular Pharmacogenomics, Cell Biology, Disease Biology, Gene Regulation and Evolution, Genetics & Pharmaceutical, Genome Biology, Molecular Genetics & Pharmaceutical, Nutrition and Phytochemistry, Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Population Health Management, Signaling & Cell Circuits, Small Molecules in Development of Therapeutic Drugs, tagged , , , , , , , , , on March 2, 2013| 2 Comments »

Cardiac Ca2+ Signaling: Transcriptional Control

Reporter: Larry H Bernstein, MD, FCAP

The other side of cardiac Ca2+ signaling: transcriptional control

A Domínguez-Rodríguez, G Ruiz-Hurtado, Jean-Pierre Benitah and AM Gómez

  • Ca2+ is not only a key element in excitation-contraction coupling (EC coupling), but
  • it is also a pivotal second messenger in cardiac signal transduction,
  • being able to control processes such as
    • excitability,
    • metabolism, and
    • transcriptional regulation.

Front. Physio. 2012; 3:452.                 http://dx.doi.org/fphys.2012.00452/
http://www.fphys.com/The other side of cardiac Ca2+ signaling: transcriptional control

calcium release calmodulin

calcium release calmodulin

English: A rendition of the CaMKII holoenzyme ...

English: A rendition of the CaMKII holoenzyme in the (A) Closed and the (B) Open conformation (Photo credit: Wikipedia)

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