Abstract 85: A Novel Mitochondrial Targeted Fusion Protein Containing Endonuclease III Protects the Heart Against Myocardial Infarction and Pressure Overload Heart Failure
Background: Oxidative stress is a primary cause of mitochondrial DNA (mtDNA) damage and plays a role in myocardial cell death. mtDNA repair enzymes are crucial for mtDNA repair and cell survival. We tested the efficacy of a novel, mitochondrial targeted fusion protein that traffics Endonuclease III (Exscien1-III) in murine models of myocardial ischemia/reperfusion (MI/R) injury and transverse aortic constriction (TAC) heart failure (HF). We previously demonstrated that Exscien1-III administered at R reduced myocardial infarct size and preserved left ventricular ejection fraction (LVEF) following MI/R. We hypothesized that delayed administration of Exscien1-III would promote mtDNA repair and protect the myocardium against MI/R and TAC heart failure.
Methods: Male C57/BL6J (10-12 wks) were subjected to 45 min of MI and 24 hrs of R. Exscien1-III (4 mg/kg, i.p., n=13) or vehicle (VEH, n=13) was administered 30 min after R. Male C57/BL6J were subjected to TAC (27 g needle) and Exscien1-III (4 mg/kg/d, i.p., n=10) or VEH (n=6) were administered starting at 3 wks post TAC. Echocardiography was performed at baseline and following TAC to assess LVEF.
Results: Exscien1-III reduced myocardial INF/AAR by 24% (p < 0.05 vs. VEH). Exscien1-III preserved LVEF (49.1 ± 4.0% vs. 32.9 ± 3.2%, p < 0.01) and reduced LV dilation (LVEDD/LVESD; 3.8/2.8 vs. 4.4/3.4, p < 0.05) at 8 wks compared to vehicle.
Conclusion: These results demonstrate that delayed administration of Exscien1-III significantly attenuates myocardial cell death and preserves LV function in acute MI and HF. Studies are currently underway to define the molecular mechanisms involved in Exscien1-III induced cardioprotection.
Author Disclosures: J.M. Bradley: None. H. Otsuka: None. C.L. Organ: None. S. Bhushan: None. D.J. Polhemus: None. G.L. Wilson: 7. Ownership Interest; Significant; Founder; Ownership stock in CardiEXCSCIEN. D.J. Lefer: 7. Ownership Interest; Significant; Ownership stock in CardiEXCSCIEN.
- © 2015 by American Heart Association, Inc.