Mitochondrial oxidative stress and dysfunction in myocardial remodelling.
Recent experimental and clinical studies have suggested that oxidative stress is enhanced in myocardial remodelling and failure. 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. 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 myocardial remodelling and failure. 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 also prevented. Therefore, 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.
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan. htsutsui@med.hokudai.ac.jp
Hiroyuki
H
Tsutsui
Shintaro
S
Kinugawa
Shouji
S
Matsushima
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015316:Genetic Therapy; D005979:Glutathione Peroxidase / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D006609:High Mobility Group Proteins / Q000378:metabolism; D006801:Humans; D008929:Mitochondria, Heart / Q000201:enzymology / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D054464:Peroxiredoxins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D020257:Ventricular Remodeling / Q000235:genetics
D000975:Antioxidants; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C499631:TFAM protein, human; C081930:Tfam protein, mouse; D014157:Transcription Factors; D054464:Peroxiredoxins; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase