Abstract 13860: The Mitochondria-targeted Antioxidant Therapy Improves Age-related Cardiovascular Dysfunction

Abstract

Senescence is a major factor to increase oxidant stress in mitochondria, which contributes to the pathogenesis of heart diseases. We postulated that scavenging effect of superoxide targeted in mitochondria would have benefit in the aged heart. Increased levels of superoxide and NADPH oxidase activity were appeared in cardiac myocytes isolated from old mice (70 W) compared to those in young mice (8 W) (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=16, respectively). In old mice treated with mitochondria-targeted antioxidant, MitoTEMPO, co-infusion using minipump (180 μg/kg/day, 28 days), levels of superoxide and NADPH oxidase activity decreased (0.2±0.2 nmol/mg protein and 342±45 RLU, p<0.01, respectively). Treatment with MitoTEMPO improved left ventricular ejection fraction from 48±5% to 62±5% (p<0.01) with old mice in echocardiography. Endothelium-dependent coronary artery vasodilation, eNOS and Sirt1 levels were lower in old mice compared to those in young mice, which were improved by MitoTEMPO treatment (n=12 each, Figures). %SOD activity in cardiac mitochondria was lower in old mice compared to that in young mice (38.7±3.7 vs. 65.0±5.2%, p<0.05), which were improved by MitoTEMPO treatment (61.2±4.1%). Treatment with MitoTEMPO in old mice improved decreased oxygen consumption rate in complex I and III of cardiac mitochondria to the level of those in young mice. Resolution of mitochondrial oxidant stress by MitoTEMPO in old mice restored cardiovascular function to the same magnitude observed in young mice. Therefore, antioxidant strategy targeting mitochondria could have therapeutic benefit in heart diseases with senescence.