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
https://pharmaceuticalintelligence.com/2013/04/14/chapter-5-mitochondria-and-cardiovascular-disease/
- Mitochondrial Metabolism and Cardiac Function, Larry H Bernstein, MD, FACP
https://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/
- Mitochondrial Dysfunction and Cardiac Disorders, Larry H Bernstein, MD, FACP
https://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-dysfunction-and-cardiac-disorders/
- Reversal of Cardiac mitochondrial dysfunction, Larry H Bernstein, MD, FACP
https://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). https://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
https://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
https://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
https://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
https://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
https://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
https://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
https://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
https://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
https://pharmaceuticalintelligence.com/2013/04/14/chapter-5-mitochondria-and-cardiovascular-disease/
Mitochondrial Metabolism and Cardiac Function, Larry H Bernstein, MD, FACP
https://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/
Mitochondrial Dysfunction and Cardiac Disorders, Larry H Bernstein, MD, FACP
https://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-dysfunction-and-cardiac-disorders/
Reversal of Cardiac mitochondrial dysfunction, Larry H Bernstein, MD, FACP
https://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)
Dr. Larry
Thank you for the last four papers on Mitochondria and CVD.
I read them all and it was a great pleasure to realize what important a chapter we have created for CVD 1,2,3.
Please review the ADDITIONS and the format changes I made to the References/Bioblio section at the end.
Please USE this one as a master for your other posts this week on Mitochondria and CVD. Use this Master list to select what belongs to each of the four.
Please note this is the SOP for Credit attribution and for Referencing related articles on THIS open access online scientific journal.
GREAT WORK!! our work on Genomics and CVD and NO e-Book are to be here, now they are. Endothelin, my 3 posts have left no stone unturned! are to be here, now they are.
Please consider (after) we will complete the three co-curated papers for CVD 1,2,3 to write ONE article from a Science History perspective of Physiology on the Starling Heart Model and its impact on CVD Research
http://www.google.com/#output=search&sclient=psy-ab&q=Starling+Heart+Model&oq=Starling+Heart+Model&gs_l=hp.3…4959.12470.0.12917.20.19.0.1.1.2.773.3369.0j17j4-1j0j1.19.0…0.0…1c.1.9.psy-ab.gKPpo-FJ1Nc&pbx=1&bav=on.2,or.r_qf.&bvm=bv.45175338,d.dmQ&fp=868f428666fb8097&biw=1314&bih=749
Thank you again for the being a master waiver of Biochemistry, Physiology, Histology, Pathphysiology, Genomics, Clinical Pharmacology and above all for sharing with your e-Readers your Critical Thinking and the finest synthesis written on the mechanics of cardiac energy demand, supply and the GAP causing dysfunction.
Since I commissioned Dr. Ritu in 7/2012 to write the first article on Mitochonrdia, much thought on this topic was devoted by our team. I reread hers in preparation for reading your four articles, and enjoyed it so very much followed by your beautiful cognitive clarity and written expressive precisive style.
Special thanks for the Tribute to Prof. Bing. I owe my gratitude to my Professor of Physiology as I expressed in:
https://pharmaceuticalintelligence.com/founder/autobiographical-annotations-tribute-to-my-professors/
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