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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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
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Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
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.
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.
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.