The mechanisms by which the cardiac myocyte (CM) senses mechanical changes and converts it to biochemical and functional effects, are poorly understood. Two areas within the CM that appear critical for proper mechanotransduction are the costamere with its resident integrins (ITGs), and caveolae, flask-shaped membrane invaginations with associated Caveolin (Cav) proteins. We and others have begun to show the importance of CM ITGs and Cav proteins in transducing mechanical signals, and that reduced expression and/ or mutation of ITGs and Cav3 can cause cardiomyopathies. How 1 ITGs and Cav-3 functionally interact and by what mechanisms their coordinated responses transduce mechanical signals in the CM are unknown. We have generated 1 ITG CM-specific knockout (KO) (termed 1cKO), Cav-3KO and CM-specific ITG and Cav-3 transgenic (Tg) mouse models. Our preliminary data shows that 1 ITG and Cav-3 co-localize and co-immunoprecipitate in the adult CM and that increased expression of ITGs and Cav-3 proteins in CMs can both preserve myocardial function when the heart is challenged with an increased mechanical load. Based on this data, we formulated our overall hypotheses that: A) 1 ITGs and Cav-3 have cooperative properties in organization of proteins required for CM mechanotransduction and B) that increased expression of both of these proteins in the CM will protect the heart challenged with an increased hemodynamic load from HF. We will pursue this with 3 aims using loss and gain of function approaches: 1) Determine roles of 1 ITGs and caveolin-3 in mechanotransductive responses of the myocardium by use of Cav3 null and 1 ITG cardiac myocyte specific knockout mice alone, or in combination. We will evaluate how acute and chronic mechanically mediated signals are altered when ITGs, Cav-3 or both proteins are lost from the CM and how loss of these proteins modifies the remodeling process as the heart hypertrophies and evolves towards a HF phenotype. 2) Define the interactions which direct cooperative mechanical signaling of cardiomyocyte 1 ITG and Cav-3. Direct interactions between ITGs and Cav3, with costameric and cytoskeletal proteins will be assessed. Proteomics will then identify novel proteins which interact with ITGs or Cav3, and how proteins in the caveolar and non-caveolar biochemical fraction of the CM change with hemodynamic challenge. 3) Determine how Tg overexpression of Cav-3 and/ or 1 ITGs alters mechanical responses, and delays or protects the heart from cardiac failure in the face of hypertrophic induction. This will allow us to directl test the potential therapeutic roles of Cav3 and 1 ITGs in the mechanically challenged myocardium. Clinical Significance: HF of varied causes is found in a large number of patients, necessitating frequent inpatient and outpatient care. Identification of root causes of cardiac dysfunction and importantly, studies which could lead to novel therapeutics of this common disease, are essential, and will be the focus of this proposal.
This proposal aims to advance our understanding of how the heart responds to excessive mechanical load, a process that frequently can lead to heart dysfunction. Studies in the grant will focus on two protein families, integrins and caveolins, which we propose both act as important modulators of this process. We will explore how these proteins function in the heart and if they may be used as novel therapies to prevent heart failure.
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