TRPC Channel Regulation of Cardiac Hypertrophy and Contractility

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Myocardial infarction (MI) is a major cause of mortality and morbidly in the US. Patients that have suffered an MI (heart attack) are usually released from the hospital with a stable hemodynamic profile but with a dead portion of their heart (the infarct zone). After an MI there are major structural and functional remodeling of the heart that ultimately produce a dilated heart with poor contractile performance, culminating in congestive heart failure (HF). Novel therapies that reduce post MI structural and functional remodeling would reduce HF. Recent studies suggest that abnormalities in calcium (Ca) regulation within different portion of cardiac myocytes, termed microdomains, cause abnormalities in myocyte structure and function. In particular, there is evidence that the Ca signaling that induces pathological remodeling and contractile disturbances occurs within unique "signaling" and "excitation-contraction coupling" microdomains that contain a poorly understood class of canonical transient receptor potential (TRPC) channels. TRPC channel expression and activity are increased after MI and their activity has been linked to pathological hypertrophy and poor contractility. This project seeks to reduce excess TRPC channels activity to improve cardiac structure and function after MI. The Specific Aims are: 1) To determine how TRPC channels interact with LTCCs and other Ca regulatory proteins within separate signaling and EC coupling microdomains to cause pathological hypertrophy and depressed contractility in cardiac disease. 2) To better characterize microdomain signaling by defining novel TRPC-LTCC partners, and 3) To determine if inhibition of TRPC activity after MI (expression of a dominant negative (dn) TRPC in transgenic mice and to begin translational studies with AAV6-dnTRPC in pigs) improves cardiac structure and function. This research will develop novel approaches to determine if reducing excess TRPC channel function after MI can improve cardiac structure and function. The projects build from fundamental discovery science to testing of novel therapeutics in a large animal model with essential human characteristics.