Abstract 1253: Inhibition of Ischemic Cardiomyocyte Apoptosis Through Targeted Ablation of Bnip3 Restrains Post-infarction Remodeling
Cardiomyocyte apoptosis contributes to early infarct expansion and late global left ventricular (LV) dysfunction after myocardial infarction. Bnip3, a proapoptotic BH3-only Bcl2 family protein, is transcriptionally upregulated in cardiomyocytes by hypoxia. We hypothesized that Bnip3 mediated cardiomyocyte apoptosis contributes to post-infarction LV remodeling. We used gene targeting and conditional overexpression to evaluate effects of Bnip3 on in vivo cardiomyocyte apoptosis, and determine the consequences of ablating murine Bnip3 (KO) on cardiomyocyte death, infarct size, and ventricular remodeling after surgical ischemia-reperfusion (IR) injury induced by reversible LAD artery occlusion for 60 minutes. Bnip 3 KO did not affect hearts of unstressed mice. After IR, Bnip3 KO mice had no differences in mortality, early infarct size (at 24 hours by gadolinium enhanced MRI) or late infarct size (at 3 weeks by MRI and pathology) as compared to wild type (WT). Two days after IR, apoptosis was significantly diminished in Bnip3 KO peri-infarct myocardium (6.7±0.8% n=6 vs 11.5±1.3% in WT, n=7; P=0.011) and remote myocardium (3.7±0.7% vs 6±0.4% in WT; P=0.014). Three weeks after IR, Bnip3 KO mice exhibited preserved global ventricular performance compared with systolic dysfunction in WT (change in LVEF from 24 hours to 3 weeks: 11±8% vs –20±7 in WT, n=8 –9; p=0.015) and significantly diminished LV dilation compared with WT (change from 24 hours to 3 weeks in LV end-diastolic volume: 46+11% vs 108+17 in WT; P=0.007 and end-systolic volume:35±20% vs 181±41 in WT; P= 0.047). These processes suggest myocardial salvage by apoptosis inhibition following IR injury in Bnip3 KO mice. Forced cardiac expression of Bnip3 increased cardiomyocyte apoptosis in unstressed mice (1.21±0.14% vs 0.17±0.02 in controls, n=4; P=0.029), causing progressive LV dilation and diminished systolic function that recapitulates Bnip3-mediated post-IR remodeling. In conclusion, post ischemic cardiomyocyte apoptosis medicated by Bnip3 is a major determinant of ventricular remodeling in the infracted heart.