Caveolae, T-type Calcium Channels and Cardiac Hypertrophy

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DESCRIPTION (provided by applicant): Cardiac hypertrophy is a major risk factor predictive of cardiovascular diseases and mortality and exists in about 10% of the general population. Myocardial hypertrophy predisposes individuals to arrhythmia, heart failure and sudden death. Cardiac hypertrophy is associated with structural, electrical, and mechanical dysfunctions resulting from persistent increase in the intracellular Ca2+ levels leading to arrhythmia and heart failure during this disease. In the adult heart at the cardiomyocyte level, Ca2+ signaling and contraction are initiated by the activation of L-type Ca2+ channels. However, the induction of pathological hypertrophic Ca2+ signaling results from the re-expression and activation of fetal T-type Ca2+ channels (TTCC). But, the mechanism of altered Ca2+ signaling in cardiac hypertrophy is not known. Caveolae containing scaffolding protein caveolin-3 (Cav-3) organize multi-protein signaling complexes and provide temporal/spatial regulation of intracellular Ca2+ in cardiomyocytes. Our preliminary data show that the cardiac TTCCs are localized to caveolae and associate with caveolin-3 and regulate their function in the ventricular myocytes. Thus caveolae and caveolin-3 could impact the Ca2+ signaling through functional regulation of cardiac TTCCs during cardiac hypertrophy. This proposal will address the following specific aims: 1) Determine the impact of cardiac hypertrophy, specifically sub cellular remodeling, on the alteration of caveolar macromolecular signaling proteins and regulation Ca2+ signaling through TTCCs 2) Determine the role of caveolin-3 in modulation of TTCC isoforms and differential regulation of unique signaling pathways during cardiac hypertrophy 3) Define the functional role of caveolin-3 and caveolae in the development of pathological cardiac hypertrophy The long-term goal of this work is to identify novel signaling mechanisms relevant to cardiac protection during cardiac hypertrophy. Our studies will define the role of caveolae and Cav-3 in cardiac protection from the level of the cardiac myocyte to the whole animal. The insights gained from this work will have significant implications for development of therapeutic modalities in patients with pathological hypertrophy and heart failure. PUBLIC HEALTH RELEVANC: Heart disease is the leading cause of death in the United States with an estimated 1 of every 3 deaths. Cardiac hypertrophy is a major risk factor predictive of several types' cardiac diseases including, myocardial infarction, heart failure and sudden death. Certain proteins such as caveolins and Ca2+ channels found in the heart control the cardiac contractile function and could offer protection during hypertrophy. Our goal in this study is to identify novel signaling mechanisms and discover key proteins involved in protection against pathological cardiac hypertrophy so effective therapies for disease prevention can be designed.