A Novel Mitochondrial DNA Repair Enzyme Attenuates Maladaptive Remodeling and Preserves Cardiac Function in Heart Failure

Background: Oxidative stress results in mitochondrial DNA (mtDNA) damage and contributes to myocardial cell death. mtDNA repair enzymes are crucial for mtDNA repair and cell survival. We investigated a novel, mitochondrial-targeted fusion protein (Exscien1-III) containing endonuclease III in myocardial ischemia/reperfusion (MI/Rep) injury and transverse aortic constriction (TAC) induced heart failure. Methods and Results: Male C57/BL6J mice (10-12 wks) were subjected to 45 min. of MI and either 24 hrs or 4 wks of R. Exscien1-III (4 mg/kg, i.p.) or vehicle (VEH) was administered at the time of R. Male C57/BL6J mice were subjected to TAC and either Exscien1-III (4 mg/kg, i.p) or VEH was administered daily starting at 3 wks post-TAC and continued for 12 wks. Echocardiography was performed to assess left ventricular (LV) structure and function. Exscien1-III reduced myocardial infarct size (p < 0.01) at 24 hrs of R. and preserved LV ejection fraction at 4 wks post MI. Exscien1-III attenuated TAC-induced LV dil...