Abstract 17970: Metabolic Support of Mitochondrial Complex I with Yeast Ndi1 Evokes Significant Cardioprotection in the in vivo Rat Model of Acute Myocardial Infarction
Lethal myocardial ischemia-reperfusion injury has been attributed in part to mitochondrial respiratory dysfunction (including damage to Complex I) and the resultant excessive production of reactive oxygen species. Recent evidence has shown that Ndi1 (the single-subunit protein that serves as the surrogate for Complex I in yeast), transduced by addition of the TAT-conjugated protein to culture media and buffer, can preserve mitochondrial function and attenuate ischemia-reperfusion injury in isolated cardiomyocytes and isolated buffer-perfused hearts. However, the in vivo efficacy of this novel metabolic strategy to salvage ischemic-reperfused myocardium has, to date, not been explored. To address this issue, TAT-conjugated Ndi1 and TAT-conjugated placebo control protein were synthesized using a cell-free (non-bacterial) system. After confirming the identity of the proteins by immunoblotting, rats were randomly assigned to receive intraperitoneal injection of either TAT-Ndi1 or TAT-placebo. Two hours post-treatment, all animals underwent 45 min coronary artery occlusion followed by 2 hours of reperfusion. Infarct size was delineated by tetrazolium staining and normalized to the volume of at-risk myocardium (the primary determinant of infarct size in this model), with all analysis conducted in a blinded manner. Risk region was comparable in the two cohorts, averaging 28-32% of the total left ventricular weight (p=ns). Pre-ischemic administration of TAT-Ndi1 was, however, associated with profound cardioprotection: infarct size in TAT-Ndi1-treated rats was 25+7%* of the myocardium at risk, significantly smaller than the value of 63+5% seen in the TAT-placebo control group (mean + SEM; *p<0.01 versus control). These results provide the first in vivo evidence that yeast Ndi1 can provide metabolic support to ischemic-reperfused myocardium and reduce myocardial infarct size. Moreover, these data suggest that metabolic support of mitochondrial proteins may provide a novel molecular strategy to protect the human heart against planned ischemia-reperfusion events.
- © 2011 by American Heart Association, Inc.