Abstract 15511: A Novel Mitochondrial Targeted DNA Repair Enzyme Attenuates Maladaptive Myocardial Remodeling and Preserves Cardiac Function in Heart Failure

Abstract

Background: Sustained increases in mitochondrial oxidative stress results in mitochondrial DNA (mtDNA) damage further worsening oxidative damage and cellular injury. These cellular events are pivotal in development and progression of myocardial damage and heart failure. We investigated the effects of a novel mitochondrial targeted fusion protein that traffics endonuclease III (Exscien1-III) and repairs mtDNA in the setting of pressure overload heart failure. Methods: Male C57/BL6J mice (n=10) were subjected to transverse aortic constriction (TAC; 27 g needle) and Exscien1-III (4 mg/kg/d, i.p.) or VEH were administered daily starting at 3 wks post TAC. Left ventricular (LV) function (Vevo 2100) was assessed at baseline and biweekly for 12 weeks post TAC. At the 12 wk endpoint, mice were sacrificed and hearts were collected for biochemical and molecular assessment of cellular injury. Results: Exscien1-III significantly attenuated TAC-induced LV dilation at 12 wks post TAC (LVEDD: 3.9 ± 0.1 vs. 4.6 ± 0.1 mm, p < 0.05; LVESD: 3.1 ± 0.2 vs. 3.9 ± 0.1 mm, p < 0.05) compared to VEH. Exscien1-III displayed a reduced LV wall thickness (LVPWd: 1.1 ± 0.1 vs. 1.4 ± 0.1 mm, p < 0.05) at 8 wks post TAC compared to VEH. In comparison to VEH, LV ejection fraction (LVEF) was preserved in the Exscien1-III treated mice at 8-12 weeks post TAC compared to VEH (*p < 0.05; **p < 0.01). Treatment with Exscien1-III resulted in a reduction in heart weights (9.7 ± 0.4 vs. 12.15 ± 1.2 mg/mm, p < 0.05) compared to VEH. Picrosirius Red staining of LV collagen revealed that Exscien1-III significantly decreased myocardial interstitial collagen volume fraction by 55% (p < 0.05 vs. VEH). Conclusion: Delayed treatment with Exscien1-III attenuated interstitial myocardial collagen deposition and preserved LVEF following the onset of TAC-induced cardiac hypertrophy and heart failure. Current studies are underway to further investigate the mechanisms by which this novel mtDNA repair enzyme protects the failing heart.