Calcium and Cardiovascular Diseases: A Series of Twelve Articles in Advanced Cardiology

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Calcium and Cardiovascular Diseases: A Series of Twelve Articles in Advanced Cardiology

January 28, 2014 by 2012pharmaceutical

Calcium and Cardiovascular Diseases: A Series of Twelve Articles in Advanced Cardiology

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 7/18/2021

IMAGE SOURCE:

Claudio A. Hetz. Antioxidants & Redox Signaling.Dec 2007.

2345-2356. http://doi.org/10.1089/ars.2007.1793

FIG. 3. Regulation of ER calcium homeostasis by the BCL-2 protein family. Different anti- and proapoptotic members of the BCL-2 family of proteins are located at the ER membrane, where they have an important role regulating ER calcium content. BCL-2 and BCL-XL interact with the IP3R calcium channel, modulating its activity. BCL-2 has been shown to increase ER calcium leak through the IP3R because of an increase on its phosphorylation levels.

BAX and BAK have the opposite effect on ER calcium content, a function that may be further modulated by BH3-only proteins (such as PUMA and BIK). In addition, the activity of BCL-2 at the ER membrane is regulated by phosphorylation. JNK phosphorylates BCL-2, decreasing its antiapoptotic activity and increasing ER calcium content, whereas the phosphatase PP2A decreases this phosphorylation through a direct interaction. Alternatively, ER stress activates the IRE1/JNK pathway that may alter the activity of BCL-2 at the ER membrane. BI-1 is also located at the ER membrane, where it regulates calcium homeostasis.

CONCLUSIONS AND THERAPEUTIC PERSPECTIVES

I have summarized different pieces of evidence suggesting that the BCL-2 family of proteins has evolved to regulate multiple processes involved in cell survival under stress conditions. The global view of the current state of the field indicates that the BCL-2–related proteins are not only the “death gateway” keeper (as upstream regulators of caspases), but they also have multiple functions in essential processes for the cell. BCL-2–related proteins are particularly important in the physiologic maintenance of the ER, where they operate as

(a) a calcium rheostat,

(b) modulators of the UPR,

(c) regulators of ER network structure, and

(d) regulators of autophagy.

In addition, examples of a role of the BCL-2 family of proteins in cell-cycle regulation (87, 113), DNA damage responses (37, 114), and glucose/energy metabolism (16) are available, strongly supporting the notion that the BCL-2 protein family is a multifunctional group of proteins that, under normal conditions, participate in essential cellular process. In doing so, the BCL-2 protein family may represent specialized stress sentinels that actively participate in essential processes, allowing a constant homeostatic “quality control.” In response to irreversible cellular damage, particular BCL-2 family members may turn into direct activators of apoptosis.

Mutations in specific genes are responsible for a variety of neurologic disorders due to the misfolding and accumulation of abnormal protein aggregates in the brain. In many of these diseases, it has been suggested that alteration in the homeostasis of the ER contributes significantly to neuronal dysfunction.

These diseases include Parkinson’s disease (32, 84), Alzheimer’s disease (22), prion diseases (27, 28, 31), amyotrophic lateral sclerosis (ALS) (97), Huntington’s disease (63, 90) and many others (see list of diseases in 86). Consequently, the first steps in the death pathways downstream of ER stress represent important therapeutic targets. In this line of thinking, pharmacologic manipulation of the activity of the BCL-2 protein family may have beneficial consequences to treat these fatal diseases. Different small molecules and synthetic peptides are currently available with proven therapeutic applications in mouse disease models, including BCL-2 inhibitors (71), BAX channel inhibitors (29), BAX/BAK activator peptides (100, 101) and many others (see reviews in 52, 79). These drugs may be used as pharmacologic tools to manipulate the activity of stress-signaling pathways regulated by the BCL-2 protein family (i.e., autophagy, calcium metabolism, or the UPR) and their possible role in pathologic conditions.

SOURCE

Claudio A. Hetz.Antioxidants & Redox Signaling.Dec 2007.

2345-2356. http://doi.org/10.1089/ars.2007.1793

Published in Volume: 9 Issue 12: November 2, 2007

Online Ahead of Print: September 13, 2007

UPDATED on 7/1/2015

We add the following to this series:

Part XIII

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

Part I:

Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP

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

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

Part IV:

The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, ArterialSmooth 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

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

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

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

Part VIII

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

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

Part IX

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

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 – Part X

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

Part XI

Sensors and Signaling in Oxidative Stress – Part XI

Larry H. Bernstein, MD, FCAP

Part XII

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

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

Posted in Acute Myocardial Infarction, Atherogenic Processes & Pathology, Best evidence, Ca2+ triggered activation, Calcium, Calcium Signaling, Calmodulin Kinase and Contraction, Cardiomyopathy, Cardiovascular Research, Congenital Heart Disease, Electrophysiology, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, HTN, Myocardial Metabolism, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Pre-Clinical Animal Model Development, Translational Effectiveness, Translational Research, Translational Science | 2 Comments

2 Responses

on March 3, 2014 at 6:46 PM | Reply CVD Prevention and Evaluation of Cardiovascular Imaging Modalities: Coronary Calcium Score by CT Scan Screening to justify or not the Use of Statin | Pharmaceutical Intelligence

This is very insightful. There is no doubt that there is the bias you refer to. 42 years ago, when I was postdocing in biochemistry/enzymology before completing my residency in pathology, I knew that there were very influential mambers of the faculty, who also had large programs, and attracted exceptional students. My mentor, it was said (although he was a great writer), could draft a project on toilet paper and call the NIH. It can’t be true, but it was a time in our history preceding a great explosion. It is bizarre for me to read now about eNOS and iNOS, and about CaMKII-á, â, ã, ä – isoenzymes. They were overlooked during the search for the genome, so intermediary metabolism took a back seat. But the work on protein conformation, and on the mechanism of action of enzymes and ligand and coenzyme was just out there, and became more important with the research on signaling pathways. The work on the mechanism of pyridine nucleotide isoenzymes preceded the work by Burton Sobel on the MB isoenzyme in heart. The Vietnam War cut into the funding, and it has actually declined linearly since.

A few years later, I was an Associate Professor at a new Medical School and I submitted a proposal that was reviewed by the Chairman of Pharmacology, who was a former Director of NSF. He thought it was good enough. I was a pathologist and it went to a Biochemistry Review Committee. It was approved, but not funded. The verdict was that I would not be able to carry out the studies needed, and they would have approached it differently. A thousand young investigators are out there now with similar letters. I was told that the Department Chairmen have to build up their faculty. It’s harder now than then. So I filed for and received 3 patents based on my work at the suggestion of my brother-in-law. When I took it to Boehringer-Mannheim, they were actually clueless.

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on April 17, 2014 at 10:08 AM | Reply Cardiovascular Diseases and Pharmacological Therapy: Curations by Aviva Lev-Ari, PhD, RN | Pharmaceutical Intelligence

This is very insightful. There is no doubt that there is the bias you refer to. 42 years ago, when I was postdocing in biochemistry/enzymology before completing my residency in pathology, I knew that there were very influential mambers of the faculty, who also had large programs, and attracted exceptional students. My mentor, it was said (although he was a great writer), could draft a project on toilet paper and call the NIH. It can’t be true, but it was a time in our history preceding a great explosion. It is bizarre for me to read now about eNOS and iNOS, and about CaMKII-á, â, ã, ä – isoenzymes. They were overlooked during the search for the genome, so intermediary metabolism took a back seat. But the work on protein conformation, and on the mechanism of action of enzymes and ligand and coenzyme was just out there, and became more important with the research on signaling pathways. The work on the mechanism of pyridine nucleotide isoenzymes preceded the work by Burton Sobel on the MB isoenzyme in heart. The Vietnam War cut into the funding, and it has actually declined linearly since.

A few years later, I was an Associate Professor at a new Medical School and I submitted a proposal that was reviewed by the Chairman of Pharmacology, who was a former Director of NSF. He thought it was good enough. I was a pathologist and it went to a Biochemistry Review Committee. It was approved, but not funded. The verdict was that I would not be able to carry out the studies needed, and they would have approached it differently. A thousand young investigators are out there now with similar letters. I was told that the Department Chairmen have to build up their faculty. It’s harder now than then. So I filed for and received 3 patents based on my work at the suggestion of my brother-in-law. When I took it to Boehringer-Mannheim, they were actually clueless.

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