Mitochondrial Dysfunction and Cardiac Disorders
Curator: Larry H Bernstein, MD, FACP
This article is the THIRD in a four-article Series covering the topic of the Roles of the Mitochondria in Cardiovascular Diseases. They include the following;
- Mitochondria and Cardiovascular Disease: A Tribute to Richard Bing, Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2013/04/14/chapter-5-mitochondria-and-cardiovascular-disease/
- Mitochondrial Metabolism and Cardiac Function, Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/
- Mitochondrial Dysfunction and Cardiac Disorders, Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-dysfunction-and-cardiac-disorders/
- Reversal of Cardiac mitochondrial dysfunction, Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2013/04/14/reversal-of-cardiac-mitochondrial-dysfunction/
Mitochondrial Metabolism in Impaired Cardiac Function
Mitochondrial Dysfunction and the Heart
- decreased metabolic efficiency and cellular insulin resistance.
They were in fact proposed by the same researcher about 20 years apart. MTA adds
- the mitochondria and its production of free radicals
- into the concept that free-radicals damage DNA over time.
- increases oxidative stress and leads to apoptosis and mitochondrial DNA damage.
- have shown promise in patients and animal models with heart failure that will be the subject of Chapter III.
Myocardial function in hypertension
- is associated with congestive heart failure in human subjects with hypertension.
- CYP27B1,
- CYP24A1,
- VDR,
- REN and
- ACE.
- 205 subjects with hypertension and congestive heart failure,
- 206 subjects with hypertension alone and
- 206 controls (frequency matched by age and gender) were genotyped.
Heart Failure and Coronary Circulation
- with recovery of skeletal muscle phosphocreatine following exercise induced by perhexiline treatment.
- underlie a common cardiac and skeletal muscle myopathy in heart failure patients.
- increases the oxidative stress in lean body mass and in the heart itself.
- induces changes in the transcription of genes that encode proteins involved in the adaptation to hypoxia.
- GLUT1 and haemoxygenase-1 in the peri-infarct region of the heart
- a return to a pattern of fetal metabolism, in which
- carbohydrates predominate as substrates for energy metabolism.
- medium-chain acyl-CoA dehydrogenase,
- CPT-1 and
- malonyl-CoA decarboxylase
- transitioning away from fatty acid metabolism proportional to the degree of cardiac impairment.
- glycolysis and glucose oxidation
- restriction of myocardial fatty acid uptake.
- the hypoxic failing heart is no longer able to oxidize fats and may also be insulin resistant.
- proapoptotic protein BCL2/adenovirus E1B 19kDa interacting protein (Bnip)3.
- induced after 1h of hypoxia, with Bnip3 integrating into the mitochondria of hypoxic ventricular myocytes.
- opening of the permeability transition pore, leading to
- loss of inner membrane integrity and
- loss of mitochondrial mass.
Mitochondrial Dysfunction caused by Bnip3 Precedes Cell Death.
- decline in circulating levels of endothelial progenitor cells was documented 3 months following instrumentation (P<0.001).
- chronic myocardial ischemia produced a biphasic response in both
- hypoxic-inducible factor 1 and
- stromal-derived factor 1 mRNA expression.
- hypoxic-inducible factor 1 and
- stromal-derived factor 1 mRNA expression .
- vascular endothelial growth factor (10-200 ng/mL)
- and stromal cell-derived factor-1 (10-100 ng/mL) .
- were documented in a reproducible clinically relevant model of myocardial ischemia.
Nitric Oxide (NO) in Myocardial Ischemia and Infarct
- produced by nitric oxide synthases, which catalyze the reaction l-arginine to citrulline and NO.
- the calcium calmodulin complex activates the constitutive NO synthase that releases NO,
- relaxing smooth muscle cells through activation of guanylate cyclase and the production cGMP.
- ATP production
- oxidative phosphorylation
- DNA synthesis.
- causes extensive vasodilation and hypotension.
- (macrophages) in the myocardium 3 days after onset of ischemia.
- as well as the coronary arterial–venous difference.
- production of NO by inflammatory cells (macrophages) in the heart.
- the result of their increased release from infarcted heart during the inflammatory phase of myocardial ischemia.
- involving the fission/fusion genes as seen in inherited maladies like Charcot–Marie–Tooth disease.
- manifest until the development of blindness.
The OPA1-mutant mice survived more than 1 year and appeared healthy.
- reduced ability to respond to high-stress disease states such as myocardial infarction and sepsis.
- the lack of response to isoproterenol or to ischemia/reperfusion injury,
- should be screened for abnormalities of cardiac function.
Mitochondrial Dysfunction and mtDNA Instability. http://jaha.ahajournals.org/content/1/5/e003012.full
Oxidative Stress and Mitochondria in the Failing Heart
- superoxide,
- hydroxyl radicals and
- hydrogen peroxide,
- mitochondrial electron transport,
- NADPH oxidase and
- xanthine dehydrogenase/xanthine oxidase.
- electron accumulation in the ET chain as the complexes become highly reduced.
- enhanced in heart failure because of electron leak, and complexes I and II
- are implicated as the primary sites of this loss.
- developed progressive congestive heart failure
- with defects in mitochondrial respiration.
- characterized by decreased ATP levels,
- impaired contractility,
- dramatically restricted exercise capacity and
- decreased survival.
- manganese5,10,15,20-tetrakis-(4-benzoic acid)-porphyrin.
- of pressure overload-induced oxidative stress and heart failure and in wild-type mice subjected to pressure overload.
- functional impairment and
- morphological disorganization
- the modulation of mitochondrial electron transport itself.
- preventing electron accumulation at complex III and
- the Fe–S centres of complex I, and may therefore
mtDNA, Autophagy, and Heart Failure
- inflammatory responses in cardiomyocytes and
- is capable of inducing myocarditis and dilated cardiomyopathy.
- infiltration of inflammatory cells
- increased messenger RNA expression of inflammatory cytokines
- accumulation of mitochondrial DNA deposits in autolysosomes in the myocardium.
- attenuated the development of cardiomyopathy in DNase II-deficient mice.
- improved pressure overload-induced cardiac dysfunction and
- inflammation even in mice with wild-type Dnase2a alleles.
Mitochondrial Dysfunction Increases Expression of Endothelin-1 and Induces Apoptosis
- preproendothelin-1 gene expression and apoptosis.
- increase in DNA laddering, an indication of apoptosis.
- mimics some of the pathophysiological features of heart failure in vivo, and that ET-1 may have a role in myocardial dysfunction
- with impairment of mitochondria in the failing heart.
Summary
- the progression of congestive heart failure (CHF).
- essential for the mechanical activity and the Starling Effect of the heart.
- substrate utilization and
- oxidative phosphorylation,
Acta Biomater. 2012 Nov 2. http://dx.doi.org/pii: S1742-7061(12)00530-2. 10.1016/j.actbio.2012.10.038. http://www.ncbi.nlm.nih.gov/pubmed/23128157
Other Related articles published on this Open Access Scientific Journal, include the following:
Perspectives on Nitric Oxide in Disease Mechanisms: The Nitric Oxide Discovery, Function, and Targeted Therapy Opportunities, 2013, Aviral Vatsa, PhD and Larry H Bernstein, MD, FACP, Editors, Amazon e-Books (forthcoming). http://pharmaceuticalintelligence.com/biomed-e-books/perspectives-on-nitric-oxide-in-disease-mechanisms-v2/
Mitochondria: More than just the “powerhouse of the cell” Ritu Saxena, Ph.D. Consultants: Aviva Lev-Ari, PhD, RN and Pnina G. Abir-Am, PhD 7/9/2012
Mitochondrial dynamics and cardiovascular diseases, Ritu Saxena, PhD 11/14/2012
http://pharmaceuticalintelligence.com/2012/11/14/mitochondrial-dynamics-and-cardiovascular-diseases/
Mitochondrial Damage and Repair under Oxidative Stress, Larry H Bernstein, MD, FACP 10/28/2012
http://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/
Mitochondria: Origin from oxygen free environment, role in aerobic glycolysis, metabolic adaptation, Larry H Bernstein, MD, FACP 9/26/2012
Ca2+ signaling: transcriptional control, Larry H Bernstein, MD, FACP 3/6/2-13
http://pharmaceuticalintelligence.com/2013/03/06/ca2-signaling-transcriptional-control/
MIT Scientists on Proteomics: All the Proteins in the Mitochondrial Matrix identified, Aviva Lev-Ari, PhD, RN 2/3/2013
http://pharmaceuticalintelligence.com/2013/02/03/mit-scientists-on-proteomics-all-the-proteins-in-the-mitochondrial-matrix-identified/
Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function, Larry H Bernstein, MD, FACP 9/16/2012
http://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-a-concomitant-influence-on-mitochondrial-function/
Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis, Larry H Bernstein, MD, FACP 2/14/2013
http://pharmaceuticalintelligence.com/2013/02/14/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-proteolysis-and-cell-apoptosis-reconsidered/
Low Bioavailability of Nitric Oxide due to Misbalance in Cell Free Hemoglobin in Sickle Cell Disease – A Computational Model Anamika Sarkar, PhD 11/9/2012
http://pharmaceuticalintelligence.com/2012/11/09/low-bioavailability-of-nitric-oxide-due-to-misbalance-in-cell-free-hemoglobin-in-sickle-cell-disease-a-computational-model/
The rationale and use of inhaled NO in Pulmonary Artery Hypertension and Right Sided Heart Failure, , Larry H Bernstein, MD, FACP 8/20/2012
Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination? Aviva Lev-Ari, PhD, RN 10/19/2012
Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation, Aviva Lev-Ari, PhD, RN 10/4/2012
Inhibition of ET-1, ETA and ETA-ETB, Induction of NO production, stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): cEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography, Aviva Lev-Ari, PhD, RN 10/4/2012
Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013, L H Bernstein, MD, FACP and Aviva Lev-Ari,PhD, RN 3/7/2013
Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production, Aviva Lev-Ari, PhD, RN 7/19/2012
Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.
Aviva Lev-Ari, PhD, RN 10/30/2012
Cholesteryl Ester Transfer Protein (CETP) Inhibitor: Potential of Anacetrapib to treat Atherosclerosis and CAD, Aviva Lev-Ari, PhD, RN 4/7/2013
Hypertriglyceridemia concurrent Hyperlipidemia: Vertical Density Gradient Ultracentrifugation a Better Test to Prevent Undertreatment of High-Risk Cardiac Patients, Aviva Lev-Ari, PhD, RN 4/4/2013
Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore, Aviva Lev-Ari, PhD, RN 4/3/2013
High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk, Aviva Lev-Ari, PhD, RN 3/31/2013
Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes, Aviva Lev-Ari, PhD, RN 11/13/2012
Sulfur-Deficiciency and Hyperhomocysteinemia, L H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2013/04/04/sulfur-deficiency-and-hyperhomocusteinemia/
Predicting Drug Toxicity for Acute Cardiac Events, L H Bernstein, MD, FACP
Amyloidosis with Cardiomyopathy, L H Bernstein, MD, FACP
Mitochondria and Cardiovascular Disease: A Tribute to Richard Bing, Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2013/04/14/chapter-5-mitochondria-and-cardiovascular-disease/
Mitochondrial Metabolism and Cardiac Function, Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/
Mitochondrial Dysfunction and Cardiac Disorders, Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-dysfunction-and-cardiac-disorders/
Reversal of Cardiac mitochondrial dysfunction, Larry H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2013/04/14/reversal-of-cardiac-mitochondrial-dysfunction/
Related articles
- Macrophage Migration Inhibitory Factor Inhibition Is Deleterious for High-Fat Diet-Induced Cardiac Dysfunction (plosone.org)
- L-carnitine significantly improves patient outcomes following heart attack (eurekalert.org)
- Mitochondrial Disorders Overview (geneticamedicala.wordpress.com)
- An Appraisal of Human Mitochondrial DNA Instability: New Insights into the Role of Non-Canonical DNA Structures and Sequence Motifs (plosone.org)
- Reversal of cardiac mitochondrial dysfunction(pharmaceuticalintelligence.com)
- Dynasore Protects Mitochondria and Improves Cardiac Lusitropy in Langendorff Perfused Mouse Heart(plosone.org)
- Mitochondrial metabolism and cardiac function(pharmaceuticalintelligence.com)
- Succinate Dehydrogenase Upregulation Destabilize Complex I and Limits the Lifespan of gas-1 Mutant(plosone.org)
-
- CHAPTER 5. Mitochondria and Cardiovascular Disease(pharmaceuticalintelligence.com)
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette