Targeting Cell Death to Prevent Ventricular Remodeling and Heart Failure

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DESCRIPTION (provided by applicant): The common cellular event that defines both myocardial infarction and the progression from compensated cardiac hypertrophy to decompensated heart failure is death of cardiomyocytes. In acute infarction, cardiomyocyte necrosis is inevitable due to oxygen/nutrient deprivation, but is followed by a wave of cell-autonomous death, or apoptosis, in the peri-infarct region. Likewise, hemodynamically stressed hearts first undergo hypertrophy, but ultimately fail in part due to apoptotic loss of cardiac myocytes. Importantly, hypertrophy develops in the surviving myocardium after an acute infarct to counterbalance increased hemodynamic load; and ischemia due to lack of angiogenesis is observed in decompensation of pressure overload hypertrophy, thus subjecting hearts to both ischemic and hypertrophic stress as a final common pathway. Therefore in both cases, effective targeting of apoptosis has the potential to retain functional myocardium. This proposal will examine the Hypothesis that cardiomyocyte apoptosis is induced by specific stress-reactive pro-apoptotic factors of the BH3 subfamily of Bcl2 proteins, and that combinatorially targeting the relevant factors in cardiac disease can be an effective means of salvaging myocardium and preventing adverse ventricular remodeling. In published and preliminary experiments we have identified two closely related BH3-only proteins, Bnip3 (Bcl-2/adenovirus E1B 19 kDa interacting protein) and Bnip3-like protein X (Nix), which are expressed in the myocardium, which can cause cellular apoptosis, and most importantly, which are specifically upregulated in myocardial ischemia (Bnip3) and cardiac hypertrophy (Nix). We have created viable mouse models in which the expression of each factor can be experimentally regulated through forced conditional transgenesis and germ-line or cardiac-specific gene ablation. In Specific Aim #1, we will test the hypothesis that Bnip3- and Nix-induced cardiomyocyte apoptosis contributes to adverse ventricular remodeling after myocardial infarction and myocardial ischemia-reperfusion injury. We have developed microsurgical procedures to generate myocardial infarction and ischemia-reperfusion injury in mice with combined forced cardiac expression and cardiac specific deletion of Nix and Bnip3, followed by magentic resonance imaging based serial assessment of infarct size and myocardial sturcture and function, and immunohistochemical detection of cardiomyocyte apoptosis, thus permitting us to analyze the outcomes as a function of Nix and Bnip3 expression. In Specific Aim #2, we will test the hypothesis that Nix- and Bnip3-induced cardiomyocyte apoptosis contributes to cardiomyopathic decompensation of pressure overload hypertrophy. We have developed and validated the technique of transverse aortic constriction. Thus, in these studies, mice with combined forced cardiac expression and cardiac specific deletion of Nix and Bnip3 will be subjected to pressure overload modeling and serially evaluated by noninvasive echocardiography. These studies will identify potential therapeutic targets to improve outcomes in heart failure, stemming from borh myocardial infarction and pressure overload hypertrophy. If the stated hypothesis is proved to be true, it will engender a paradigm shift change our approach to cardiomyopathies from stress-centricism, to one based on a targeting common pathophysiological events encompassing both ischemic and hypertrophic stresses. PUBLIC HEALTH RELEVANCE: Project Narrative Heart failure is a very common disease of the aging population, with the highest incidence and prevalence in the age group above 65, which is also the largest Veteran population group (more than 40%). Nearly one third of the Veterans have ischemic heart disease and another third have hypertension and/or aortic valve stenosis, which cause heart failure. This proposal critically examines the role of two cardiac expressed proteins, Bnip3 and Nix, in causing cardiac muscle cell death in these conditions, with the potential for development of clinical therapies to salvage cardiac muscle and prevent/treat the heart failure epidemic.