Abstract 12246: Is Mitochondrial DNA Fragmentation a Major Contributor to Necrosis in Myocardial Infarction?
A fusion protein based on endonuclease III, a DNA repair enzyme with pyrimidine glycosylase/AP lyase activity, engineered to enter cells and be taken up by mitochondria (EndoIII) given to ischemic mouse hearts at reperfusion reportedly reduces infarct size (IS). We tested whether EndoIII protects ischemic myocardium by preventing mitochondrial DNA (mtDNA) fragmentation. Extracellular mtDNA can be mistaken for bacterial DNA by neighboring cells and trigger an injurious inflammatory response which in the heart could lead to spreading necrosis. In situ rat hearts were subjected to 30-min coronary occlusion/2-h reperfusion. Intravenous EndoIII just prior to reperfusion reduced IS from 43.8±1.4% of risk zone in control hearts to 24.0±1.3% with no detectable hemodynamic effect. Enzymatically inactive EndoIII offered no protection. EndoIII’s protection was comparable to that of the platelet P2Y12 antagonist cangrelor (25.0±1.8% of risk zone). Because loading with a P2Y12 receptor blocker to inhibit platelets is currently standard of care for treatment of myocardial infarction (MI), we tested whether EndoIII could further reduce IS in rats treated with a maximally protective dose of cangrelor. The combination reduced IS to 15.1±0.9%, significantly smaller than that seen with either cangrelor or EndoIII alone. Protection from cangrelor but not EndoIII was abrogated by blockade of phosphatidylinositol-3 kinase or adenosine receptors indicating differing cellular mechanisms. If released mtDNA fragments induce spreading necrosis in the reperfused tissue, then degrading extracellular mtDNA with deoxyribonuclease I (DNase I) should prevent it. Intravenous DNase I at reperfusion mimicked EndoIII’s protection supporting the hypothesis. DNase I protection was additive to that of cangrelor and it also protected Krebs-perfused hearts indicating blood cells were not involved in its protection. Combining EndoIII and DNase I provided even greater protection presumably by protecting many of the ischemic cardiomyocytes and also by preventing necrosis spreading from those cells that EndoIII could not save. Because protection from EndoIII and DNase I can add to protection from a P2Y12 blocker, it should be effective in today’s patients with acute MI.
Author Disclosures: M.V. Cohen: None. X. Yang: None. L. Cui: None. G.L. Wilson: None. M. Alexeyev: None. M.N. Gillespie: None. J.M. Downey: None.
- © 2014 by American Heart Association, Inc.