Abstract 13035: Overexpressing Superoxide Dismutase 2 Induces Super-normal Cardiac Function by Enhancing Mitochondrial Function and Metabolic Dilation

Abstract

During heightened cardiac work, O 2 consumption by the heart increases. This increase benefits energy production via mitochondrial e − transport, but some e − “leak” from respiratory chain and yields O 2 [[Unable to Display Character: ˙]] − , which is rapidly metabolized into H 2 O 2 by SOD2. To understand the potential systemic effects of the metabolic dilator, H 2 O 2 , we studied mice with cardiac specific SOD2 overexpression, which would increase H 2 O 2 produced by the cardiac mitochondria (by 1.9 fold vs WT). To determine if this enhanced production of H 2 O 2 enhances metabolic dilation, we first evaluated the effectiveness of SOD2 overexpression to effectively enhance mitochondrial function. Mitochondria of SOD2 transgenic mice had a decreased state 3 oxygen consumption rate, but maintained the same level of ATP production; thus indicating a higher P/O ratio and bioenergetics efficiency induced by overexpressing SOD2. Mitochondria of SOD2-tg (compared to WT) produced less • O 2 − , and had lower redox activity (by EPR) and lower GSSG concentration (decreased by 37.2±4.5%). EPR analysis of the isolated mitochondria showed significant decrease of semiquinone in the SOD2-tg at the Q i site (by 69.4±9.9%), and a diminished complex I-derived protein thiyl radical(s). These results support a more reductive physiological setting of the SOD2-tg heart. Cardiac mitochondria isolated from SOD2-tg exhibited no significant differences in the respiratory control index between WT and SOD2-tg. These results support that the SOD2 overexpression is effective and results in enhanced mitochondrial function. Contrast echocardiography was employed to evaluate hemodynamic effects. Mean arterial pressure (MAP) was lower in the SOD2-tg, but was normalized by intravenous injection of catalase suggesting “spill-over” of H 2 O 2 from the myocardium in sufficient amounts to produce a systemic effect. Increasing myocardial work (norepinephrine) caused a far greater increase myocardial blood flow (MBF) per level of work in SOD2-tg compared to WT. Echocardiography indicated SOD2-tg had a significant greater ejection fraction (90±1% vs 74±2%). In conclusion, SOD2 overexpression in myocytes enhances mitochondrial function and metabolic vasodilation, leading to phenotype of super-normal cardiac function.