Abstract 1230: Overexpression Of Catalase Targeted To Mitochondria (MCAT) Attenuated Age-related Mitochondrial Damage, Left Ventricular Hypertrophy, Diastolic Dysfunction And Prolonged Mice Survival
Introduction: Age is a major risk for cardiovascular diseases. According to the mitochondrial theory of aging, reactive oxygen species (ROS) produced via mitochondrial respirations attack molecules and cause functional decline of organ that eventually leads to death. We want to investigate the hypothesis of mitochondrial ROS in cardiac aging and its contribution to survival.
Methods and Results: Overexpression of mitochondrial catalase (MCAT) protected the aged heart from oxidative damage to the mitochondria, as shown by better preserved cytochrome oxidase activity and lower rate of mitochondrial DNA mutation (by random mutation capture assay). Echocardiography was performed for 170 MCAT and littermate wild-type (WT) mice in the longevity cohort study. In the absence of hypertension, diabetes or hypercholesterolemia, we found age-dependent increases in left ventricular mass index (LVMI), decrease in Em/Am as measured by Tissue Doppler Imaging of mitral annulus, worsening of myocardial performance index (MPI) as well as increased prevalence of diastolic dysfunction in WT mice. All of the above age-related changes were significantly attenuated in MCAT littermates. These results were consistent with the pathologic findings of increased ventricular fibrosis and enlarged cardiomyocytes during aging, both of which were significantly attenuated in the old MCAT mice. Multivariate analyses revealed that the most important predictor of age-related diastolic dysfunction was the decline of cardiac SERCA2 protein, which was better preserved in MCAT. Survival analysis showed that cardiac aging risk score, defined as β1 LVMI + β2 MPI from Cox model, was an independent predictor for survival in the mouse longevity cohort (HR: 2.75, p=0.01). Cardiac aging might explain half of all-cause mortality in the cohort (estimated by attributable risk of 55%). These findings were consistent with our previous observations that MCAT mice had 21% extension of median lifespan.
Conclusion: Our study emphasizes the role of mitochondrial ROS in cardiac aging and the impact of cardiac aging on survival. These findings also suggest the potential roles of mitochondrial antioxidants in several oxidative-stress related cardiovascular diseases.