Preservation of Cardiac Function and Attenuation of Remodelling in Transient Receptor Potential Vanilloid 4 Knockout Mice Following Myocardial Infarctionnd Medical Center

Gregory H Turner,Weike Bao

doi:10.4172/2155-9880.1000366

Abstract

Transient receptor potential channel vanilloid 4 (TRPV4) is a non-selective Ca2+ permeable cation channel, recently implicated by computational methods as a key signalling component during myocardial infarction. We previously showed that pharmacological TRPV4 inhibition can prevent and resolve pulmonary edema in pre-clinical heart failure animal models. Here, we examined the impact of genetic deletion of TRPV4 (TRPV4-/-) on cardiac function, both basally and following myocardial infarction. Cardiac function was similar in wild type and TRPV4-/- mice under normal conditions. By contrast, following myocardial infarction induced by permanent ligation of the left anterior descending coronary artery, left ventricular systolic and diastolic volumes were reduced and ejection fraction was significantly improved in TRPV4-/- when compared to wild type mice. Consistent with the differences in chamber volumes between TRPV4-/- and wild type mice, myocardial infarction induced a significant increase in heart weight and left ventricular mass index in wild type, but not in TRPV4-/- mice. In a separate cohort of mice, we also investigated the effect of genetic deletion of TRPV4 on infarct size after a 30 min myocardial ischemia and 24 hours reperfusion. There were no differences in myocardial infarct size or area at risk in TRPV4-/- and wild type mice after ischemia/reperfusion injury. These results suggest that TRPV4 does not mediate acute myocardial ischemic injury, but does play an important role in ventricular remodelling known to correlate with poor outcomes following acute myocardial infarction.

Highlights

The transient receptor potential vanilloid 4 (TRPV4) channel is a polymodal-gated cationic channel that is expressed in a variety of tissues, including various epithelia, inflammatory cells, the heart, and blood vessels [1,2,3,4,5]
Our previous work has shown that pharmacological TRPV4 activation induces extensive pulmonary edema, along with a complex series of cardiovascular effects including endothelial breakdown and right sided cardiac failure [7]
We have shown that pharmacological TRPV4 inhibition can reduce pulmonary edema in experimental models of heart failure [5]

Summary

Introduction

The transient receptor potential vanilloid 4 (TRPV4) channel is a polymodal-gated cationic channel that is expressed in a variety of tissues, including various epithelia, inflammatory cells, the heart, and blood vessels [1,2,3,4,5]. TRPV4 activity has been associated with disruption of tight-junctions and increased permeability in cultured epithelial and endothelial cells [5,6,7,8]. Activation of TRPV4 by increasing vascular [9] or airway [10] pressure in intact lungs promotes formation of pulmonary edema. These observations are consistent with the established pressuresensitive activation property of the TRPV4 channel [1]. TRPV4 activation elicited a circulatory collapse associated with disruption of the endothelial permeability barrier in the lung leading to severe pulmonary edema, congestion and cardiac failure. Fibroblast TRPV4 activity has been shown to be increased in idiopathic pulmonary fibrosis patients, and is stimulated by enhanced stiffness with an ability to drive pulmonary fibrosis in mice [13]

Methods

Results

Conclusion