Larry H Bernstein, MD, FACP, Curator Pharmaceutical intelligence
Reversal of cardiac mitochondrial dysfunction
http://Pharmaceuticalintelligence.com/4_14_3013/Reversal of cardiac mitochondrial dysfunction
Mitochondrial metabolism and cardiac function
There is sufficient evidence to suggest that, even with optimal therapy, there is an attenuation or loss of effectiveness of neurohormonal antagonism as heart failure worsens. The production of oxygen radicals is increased in the failing heart, whereas normal antioxidant enzyme activities are preserved. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and can be a therapeutic target against oxidant-induced damage in the failing myocardium. Therefore, future therapeutic targets must address the cellular and molecular mechanisms that contribute to heart failure. Furthermore, since defective mitochondrial energetics and abnormal substrate metabolism are fundamental characteristics of the failing heart, we might expect that substantial beneﬁt may be derived from the development of therapies aimed at preserving cardiac mitochondrial function and optimizing substrate metabolism.
Nutrition and physiological function
Blockade of electron transport with the reversible complex I inhibitor amobarbital before ischaemia in isolated, perfused guinea pighearts decreased superoxide production and preserved oxidative phosphorylation in cardiac mitochondria, thus decreasing myocardial damage. But when ascorbic acid was administered orally to chronic heart failure
patients, there were improvements in endothelial function but no improvement in skeletal muscle energy metabolism. Angiotensin I-converting enzyme (ACE) inhibitors also appear to preserve mitochondrial function in models of heart failure, with trandolapril treatment improving cardiac energy metabolism and function in rats with chronic heart failure. Similarly perindopril treatment restored levels of the mitochondrial biogenesis transcription factors PPARg
coactivator-1a and nuclear respiratory factor-2a, and prevented mitochondrial dysfunction in rat skeletal muscle after myocardial infarction.Tissue effects of ACE inhibition, such as decreased oxidative stress and improved endothelial function, might activate intracellular signalling cascades that stimulate mitochondrial biogenesis and improve energy metabolism. Clearly, the mechanisms of metabolic regulation by existing cardioprotective agents require further investigation.
Exercise training and mitochondria in heart failure
The beneﬁcial effects of exercise in the rehabilitation of patients with heart failure are well established, with improvements observed in exercise capacity, quality of life, hospitalization rates and morbidity/mortality. There is no evidence of training-induced improvements in cardiac energy metabolism or mitochondrial function, and no modiﬁcation of myocardial oxidative capacity, oxidative enzymes, or energy transfer enzymes in exercising rats with experimental heart failure, but there is evidence of ventricular remodelling
, restored contractile function and improved intracellular calcium handling. There are also improvements in skeletal muscle oxidative capacity with increased mitochondrial density following endurance training in heart failure patients associated with alleviation of symptoms such as exercise intolerance and chronic fatigue. The mechanism underlying improvements in mitochondrial function may perhaps be a result of more effective peripheral oxygen delivery following training, alleviating tissue hypoxia and oxidative stress.
Inhibition of oxidative stress and mtDNA damage
Novel pharmacological agents are needed that optimize substrate metabolism and maintain mitochondrial integrity, improve oxidative capacity in heart and skeletal muscle, and alleviate many of the clinical symptoms associated with heart failure. The evidence for the attenuation or loss of effectiveness of neurohormonal antagonism as heart failure worsens indicates future therapeutic targets must address the cellular and molecular mechanisms that contribute to heart failure. Defective mitochondrial energetics and abnormal substrate metabolism are fundamental characteristics of the failing heart, suggesting that beneﬁt may be derived from the development of therapies aimed at preserving cardiac mitochondrial function and optimizing substrate metabolism.
is enhanced in myocardial remodelling and failure. The increased production of oxygen radicals in the failing heart with preserved antioxidant enzyme activities suggests that mitochondrial electron transport as a source of oxygen radical generation can be a therapeutic target against oxidant-induced damage in the failing myocardium. Chronic increases in oxygen radical production in the mitochondria leads to mitochondrial DNA (mtDNA) damage, functional decline, further oxygen radical generation, and cellular injury. MtDNA defects may thus play an important role in the development and progression of myocardial remodelling and failure. Reactive oxygen species induce myocyte hypertrophy, apoptosis, and interstitial fibrosis by activating matrix metallo-proteinases, promoting the development and progression of maladaptive myocardial remodelling and failure.
Oxidative stress has direct effects on cellular structure and function and may activate integral signalling molecules in myocardial remodelling and failure (Figure). ROS
result in a phenotype characterized by hypertrophy and apoptosis in isolated cardiac myocytes.
Therefore, oxidative stress and mtDNA damage are good therapeutic targets. Overexpression of the genes for peroxiredoxin-3 (Prx-3), a mitochondrial antioxidant, or mitochondrial transcription factor A (TFAM
), could ameliorate the decline in mtDNA copy number in failing hearts. Consistent with alterations in mtDNA, the decrease in mitochondrial function was prevented, proving that the activation of Prx-3 or TFAM gene expression could ameliorate the pathophysiological processes seen in mitochondrial dysfunction and myocardial remodelling. Inhibition of oxidative stress and mtDNA damage could be novel and effective treatment strategies for heart failure.
Proposed mechanisms through which overexpression of the mitochondrial transcription factor A (TFAM) gene prevents mitochondrial DNA (mtDNA) damage, oxidative stress, and myocardial remodelling and failure. In wild-type mice, mitochondrial transcription factor A directly interacts with mitochondrial DNA to form nucleoids. Stress such as ischaemia causes mitochondrial DNA damage
, which increases the production of reactive oxygen species (ROS) and thus leads to a catastrophic cycle of mitochondrial electron transport impairment, further reactive oxygen species generation, and mitochondrial dysfunction. TFAM overexpression may protect mitochondrial DNA from damage by directly binding and stabilizing mitochondrial DNA and increasing the steady-state levels of mitochondrial DNA, which ameliorates mitochondrial dysfunction and thus the development and progression of heart failure.
Heart failure is a multifactorial syndrome that is characterized by abnormal energetics and substrate metabolism in heart and skeletal muscle. Although existing therapies have been beneﬁcial, there is a clear need for new approaches to treatment. Pharmacological targeting of the cellular stresses underlying mitochondrial dysfunction, such as elevated fatty acid levels, tissue hypoxia and oxidative stress and metabolic modulation of heart and skeletal muscle mitochondria, appears to offer a promising therapeutic strategy for tackling heart failure.
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