Molecular Mechanism of Apoptotic Cardiomyopathy Cardiac myocyte apoptosis contributes to functional cardiac deterioration in experimental myocardial infarction as well as ischemic and dilated human cardiomyopathies. In pursuing our long term goal of identifying and modifying the determinants of myocardial ischemia, we previously identified an inducible cardiac apoptotic gene program that includes the BH3-only Bcl-2 family member, Nix. Our studies have demonstrated Nix upregulation in human hypertensive heart disease, and Nix functional involvement in experimental apoptotic cardiomyopathies. Nix shares structure and function with another cardiac-expressed BH3-only protein, Bnip3, which we found is specifically induced by ischemia, in contrast to Nix induction specifically during hypertrophy. Here we propose studies to test the General Hypothesis that Bnip3 and Nix are, respectively, the apical regulators of mitochondrial-dependent apoptotic responses to ischemia and hypertrophy. Our experimental approach is to define the consequences of gain and loss of Nix and/or Bnip3 on cardiomyocyte apoptosis, cardiac function, and ventricular maladaptation in ischemic and non-ischemic heart disease. We will use novel mouse lines wherein we have mutationally ablated or conditionally overexpressed Bnip3 or Nix, singly and in combination. These studies will employ cell-based and isolated perfused heart models together with studies of integrated cardiovascular physiology in the intact mouse to define mechanisms for and determine physiological relevance of the postulated Bnip3 and Nix apoptosis signaling pathways. In three Specific Aims we will test the following Specific Hypotheses: #1 Bnip3 is post- translationally activated by translocation to mitochondria during myocardial ischemia and contributes to infarct expansion by inducing apoptosis of cardiac myocytes within the ischemic zone. #2. Nix contributes to hypertrophy decompensation by being induced in, and causing apoptosis of, hypertrophied cardiac myocytes. #3. Nix increases sarcoplasmic reticular calcium available for cardiomyocyte contractility and mitochondrial permeability transition pore activation in response to apoptotic stimuli. These studies will position us to achieve, in this cycle, our long-term goal by establishing whether Nix and Bnip3 can be therapeutically targeted in order to enhance myocardial preservation through minimization of programmed cardiomyocyte loss in ischemic and non-ischemic myocardial injury. Project Narrative: Relevance This research program seeks to identify the precise role of heart muscle cell death in causing heart failure that develops after a `heart attack'or myocardial infarction caused by blockage of heart's arteries, and heart muscle thickening or hypertrophy due to high blood pressure and aortic valve narrowing. These common clinical conditions are responsible for the vast majority of heart failure cases worldwide, a leading cause of human death and suffering. In particular, this program will elucidate the role of two pro-death proteins, namely Nix and Bnip3, in causing heart muscle cell death in these conditions and form the basis for developing novel treatments targeting these specific proteins, thus preventing and/or retarding the development and progression of heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Dorn 2nd, Gerald W (2016) Parkin-dependent mitophagy in the heart. J Mol Cell Cardiol 95:42-9
Dorn Ii, Gerald W (2016) Mitochondrial fission/fusion and cardiomyopathy. Curr Opin Genet Dev 38:38-44
Dorn 2nd, Gerald W (2016) Central Parkin: The evolving role of Parkin in the heart. Biochim Biophys Acta 1857:1307-12
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Naon, Deborah; Zaninello, Marta; Giacomello, Marta et al. (2016) Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum-mitochondria tether. Proc Natl Acad Sci U S A 113:11249-11254
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Dorn 2nd, Gerald W; Kitsis, Richard N (2015) The mitochondrial dynamism-mitophagy-cell death interactome: multiple roles performed by members of a mitochondrial molecular ensemble. Circ Res 116:167-82
Dorn 2nd, Gerald W (2015) Mitochondrial dynamism and heart disease: changing shape and shaping change. EMBO Mol Med 7:865-77

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