Abstract 11543: Resolution of Mitochondrial Oxidant Stress Improves Aged-Cardiac Performance

Abstract

Senescence is a major factor to increase mitochondrial oxidant stress, which contributes to the pathogenesis of heart disease. However, the effect of antioxidant therapy on cardiac mitochondria in aged-cardiac performance remains elusive. We postulated that mitochondrial targeting of superoxide scavenging would have benefit in the aged heart. Increased levels of superoxide and NADPH oxidase activity were appeared in cardiac myocytes isolated from old mice (52W) compared to those from young mice (8W) (Superoxide: 2.6±0.4 vs. 1.2±0.2 nmol/mg protein; NADPH oxidase activity: 2654±282 vs. 1124±156 RLU, P<0.01, n=12, respectively). In old mice treated with the mitochondria-targeted antioxidant MitoTEMPO (180 μg/kg/day, 28 days) coinfusion using subcutaneously implanted minipump, levels of superoxide and NADPH oxidase activity markedly decreased (0.2±0.2 nmol/mg protein and 342±45 RLU, respectively, P<0.01) and eliminated fluorescence intensity of MitoSox Red in cardiomyocytes (from 11.2±2.1 to 0.4±1.1 arbitrary unit, P<0.01). Treatment with MitoTEMPO in old mice improved left ventricle ejection fraction (from 48±5% to 62±5%, P<0.01) and diastolic dysfunction assessed by echocardiography. Endothelium-dependent vasodilation in isolated coronary arterioles was impaired in old mice compared to that in young mice, which was improved by MitoTEMPO treatment (Figure). Mitochondria from the old mouse myocardium exhibited lower rate in complex I (-38±5%) and complex II (-34±6%) -dependent respiration compared with young mice. Supplementation of MitoTEMPO in old mice improved the respiration rates in mitochondria to the level similar to those in young mice. Resolution of mitochondrial oxidant stress by MitoTEMPO in old mice restored cardiac function and coronary vasodilative capacity to the same magnitude observed in young mice. Therefore, antioxidant strategy targeting mitochondria could have therapeutic benefit in heart diseases with senescence.