Pathophysiological Roles of the TRPV4 Channel in the Heart

Abstract

The transient receptor potential vanilloid 4 (TRPV4) channel is a non-selective cation channel that is mostly permeable to calcium (Ca²⁺), which participates in intracellular Ca²⁺ handling in cardiac cells. It is widely expressed through the body and is activated by a large spectrum of physicochemical stimuli, conferring it a role in a variety of sensorial and physiological functions. Within the cardiovascular system, TRPV4 expression is reported in cardiomyocytes, endothelial cells (ECs) and smooth muscle cells (SMCs), where it modulates mitochondrial activity, Ca²⁺ homeostasis, cardiomyocytes electrical activity and contractility, cardiac embryonic development and fibroblast proliferation, as well as vascular permeability, dilatation and constriction. On the other hand, TRPV4 channels participate in several cardiac pathological processes such as the development of cardiac fibrosis, hypertrophy, ischemia-reperfusion injuries, heart failure, myocardial infarction and arrhythmia. In this manuscript, we provide an overview of TRPV4 channel implications in cardiac physiology and discuss the potential of the TRPV4 channel as a therapeutic target against cardiovascular diseases.

Keywords: TRPV4 channels; TRPV4-KO mice; action potential; calcium homeostasis; endothelial cells; fibroblasts; heart; myocytes.

Figure 1

Schematic view of TRPV channel structures and associated ion permeation pathway. (A) Comparison of TRPV pore structures. For clarity, only two opposing subunits are shown (segment S6). Interestingly the TRPV4 upper gate is larger compared to the other members of the TRPV family (TRPV1, TRPV2 and TRPV5). (B) Homotetrameric structure of TRPV4. (C) Functional characteristics of TRPV channels (permeability ratio P_Ca/P_Na). The red square refers to the Ca²⁺ permeability of the TRPV4 channel.

Figure 2

TRPV4 expression and function model in healthy (left) and pathologic (right) cardiac cells. Under physiological conditions, TRPV4 channels (yellow channels) present a low expression level in the plasma membranes of cardiac cells. With aging, pressure overload, ischemia–reperfusion and others deleterious factors, TRPV4 exhibits increases in both expression and activity in the plasma membranes of cardiac cells, which tend towards the progression of cardiovascular diseases.