Cardiomyocyte TRPV4 and Angiotensin-II induced ventricular arrhythmia with aging

Project Summary/Abstract Transient receptor potential vanilloid, member 4 (TRPV4) is a cation channel highly expressed in cardiomyocytes with aging, and contributes to enhanced cardiomyocyte calcium cycling and hypercontractility following TRPV4 gating stimuli including osmotic stress and mechanical stretch. Excessive TRPV4 activation leads to cardiac damage and ventricular arrhythmia. Angiotensin II (AngII) is a peptide hormone critically important to cardiovascular physiology and pathology due to its regulatory effects on blood volume and pressure. In many cell types, AngII increases TRPV4 activity although the contribution of this signaling axis to cardiomyocyte calcium homeostasis is currently unknown. This renewal proposal tests the central hypothesis that TRPV4 contributes to AngII-dependent cardiomyocyte calcium signaling and ventricular arrhythmia. To test this hypothesis, we will use both a pharmacologic (TRPV4 inhibition) and genetic approach (cardiomyocyte specific TRPV4 deletion or overexpression) to examine the functional role of TRPV4 in isolated cardiomyocytes, in isolated perfused hearts, and in mice in vivo. Specific Aim 1 uses isolated cardiomyocytes and isolated perfused hearts to test the hypothesis that AngII promotes TRPV4 trafficking, increases TRPV4 activity, and enhances cardiomyocyte calcium transients during excitation-contraction coupling. Specific Aim 2 tests the hypothesis that cardiomyocyte TRPV4 contributes to AngII-induced cardiac remodeling, and examines the role of TRPV4 in hypertrophic and fibrotic remodeling following AngII excess (osmotic mini-pumps) and during biological aging. Specific Aim 3 tests the hypothesis that TRPV4 contributes to pro-arrhythmic cardiomyocyte calcium signals and ventricular arrhythmia following both acute and chronic AngII excess. The overall goal of this project is to establish TRPV4 as a therapeutic target to prevent arrhythmia with aging.