"TRPV1 is a component of the atrial natriuretic signaling complex, and using orally delivered antagonists, presents a valid therapeutic target in the longitudinal reversal and treatment of cardiac hypertrophy and heart failure".

Background Activation of the atrial natriuretic signaling pathway is intrinsic to the pathological responses associated with a range of cardiovascular diseases that stress the heart, especially those involved in sustained cardiac pressure overload which induces hypertrophy and the pathological remodeling that frequently leads to heart failure. We identify transient receptor potential cation channel, subfamily V, member 1, as a regulated component, and therapeutic target of this signaling system. Methods We undertook biochemical, calcium imaging and electrophysiological experiments to analyze interactions and regulation of TRPV1. Pressure overload cardiac hypertrophy was modeled in mice using transthoracic aortic constriction, after which TRPV1 antagonists were delivered orally, to assess any reversal in the loss of function associated with pressure overload cardiac hypertrophy. Results The data show that TRPV1 is a physical component of the natriuretic peptide A, cGMP, PKG signaling complex, interacting with the natriuretic peptide receptor 1 (NPR1), and upon binding its ligand, natriuretic peptide A (NPPA, ANP) TRPV1 activation is subsequently suppressed through production of cGMP and PKG mediated phosphorylation of the channel. Further, drug inhibition of TRPV1 suppresses chamber and myocyte hypertrophy, and improves in vivo heart function in mice exposed to chronic pressure overload induced by transverse aortic constriction, reversing pre-established hypertrophy induced by pressure load while restoring chamber function. Conclusions TRPV1 is a physical and regulated component of the natriuretic peptide signaling system, and TRPV1 inhibition may provide a new treatment strategy for treating the loss of function associated with cardiac hypertrophy and remodeling.