Mitochondrial oxidative stress, DNA damage, and heart failure

Abstract

Recent experimental and clinical studies have suggested that oxidative stress is enhanced in heart failure. The production of oxygen radicals is increased in the failing heart, whereas antioxidant enzyme activities are preserved as normal. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and also a target of oxidant-induced damage. Chronic increases in oxygen radical production in the mitochondria can lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage as well as functional decline, further oxygen radical generation, and cellular injury. Reactive oxygen species induce myocyte hypertrophy, apoptosis, and interstitial fibrosis by activating matrix metalloproteinases. These cellular events play an important role in the development and progression of maladaptive cardiac remodeling and failure. Therefore, mitochondrial oxidative stress and mtDNA damage are good therapeutic targets. Overexpression of mitochondrial transcription factor A (TFAM) could ameliorate the decline in mtDNA copy number and preserve it at a normal level in failing hearts. Consistent with alterations in mtDNA, the decrease in oxidative capacities was also prevented. Therefore, the activation of TFAM expression could ameliorate the pathophysiologic processes seen in myocardial failure. Inhibition of mitochondrial oxidative stress and mtDNA damage could be novel and potentially very effective treatment strategies for heart failure.