Mitochondrial oxidative stress in cardiac aging, pressure-overload induced cardiac hypertrophy and failure

Although mitochondrial reactive oxygen species (ROS) have been proposed as one of the causes of aging, their role in cardiac aging remains unclear. We have previously demonstrated that mice over-expressing a cDNA for human catalase targeting to the mitochondria (mCAT) are better protected from chronic ROS injury than those with catalase targeting to peroxisomes (pCAT, normal location of catalase) or nuclei (nCAT), as shown by the longer lifespan of MCAT than pCAT or nCAT mice. The work shown in this thesis shows that cardiac aging in the mouse closely recapitulates human aging: age-dependent increases in left ventricular mass index and left atrial dimension, worsening of the myocardial performance index, and a decline in diastolic function. Cardiac aging in mice is also accompanied by accumulation of mitochondrial protein oxidation, increased mitochondrial DNA mutations and deletions and mitochondrial biogenesis, increased ventricular fibrosis, enlarged myocardial fiber size, elevated cardiac Angiotensin II level, decreased cardiac SERCA2 protein and activation of the calcineurin-NFAT pathway. All of these age-related changes were significantly attenuated in mCAT mice. Analysis of survival of 130 mice demonstrated that echocardiographic cardiac aging risk scores were significant predictors of mortality. The estimated attributable risk to mortality for these two parameters was 55%. We further found that Angiotensin II, a key molecule in promoting hypertension, increases mitochondrial reactive oxygen species (ROS) in cardiomyocytes and induces cardiac protein oxidative damage and mitochondrial DNA deletions, concomitant with increased autophagy and mitochondrial biogenesis, all of which are mediated by mitochondrial ROS. This relationship is reinforced by the observation that mice that overexpress catalase targeted to mitochondria, but not mice that overexpress wild-type peroxisomal catalase are resistant to cardiac hypertrophy induced by Angiotensin II and heart failure induced by overexpression of the Galphaq receptor. Furthermore, primary damage to mitochondrial DNA, which also induced ROS, is also shown to contribute directly to the development of cardiac hypertrophy and failure. These findings demonstrate the important role of mitochondrial ROS in cardiac aging, hypertrophy and failure and support the potential application of mitochondrial antioxidants in prevention and treatment of cardiac aging and hypertensive cardiomyopathy.