Activation of Endothelial TRPV4 Exacerbates Myocardial Ischemia-Reperfusion Injury via Vascular Integrity Impairment.

BACKGROUND

Activation of transient receptor potential vanilloid 4 (TRPV4) exacerbates myocardial ischemia-reperfusion (IR) injury and is highly expressed in vascular endothelial cells. The role of TRPV4 in cardiac endothelial cells (CECs) during IR remains unclear. We hypothesized that endothelial TRPV4 contributes to postischemic vascular hyperpermeability and myocardial injury by modulating barrier function and apoptosis.

METHODS

Myocardial IR was induced in C57BL/6 wild type, global TRPV4 knockout, and tamoxifen-inducible endothelial TRPV4 knockout cells, and tamoxifen-treated controls. Primary cultured CECs (passage 3) were subjected to hypoxia-reoxygenation and treated with the TRPV4 antagonist GSK2193874 or agonist GSK101790A.

RESULTS

Mice lacking TRPV4 mice exhibited smaller infarcts, preserved endothelial integrity, decreased vascular permeability, upregulated vascular endothelial-cadherin, claudin-5, and occludin, and reduced inflammation. GSK2193874 pretreatment reproduced these protective effects, whereas TRPV4 activation worsened injury. Endothelial-specific TRPV4 knockout provided similar protection. In CECs, TRPV4 inhibition attenuated hypoxia-reoxygenation-induced permeability increases and junctional protein loss, whereas TRPV4 agonist alone increased permeability and reduced vascular endothelial-cadherin, claudin-5, and occludin. Mechanistically, TRPV4 activation increased CEC permeability via the Ca2+/protein kinase C (PKC)/Ras homolog family gene member A (RhoA)/myosin light chain (MLC) pathway and promoted apoptosis through mitogen-activated protein kinase-protein kinase B signalling.

CONCLUSIONS

Activation of endothelial TRPV4 CECs exacerbates post-IR vascular hyperpermeability and myocardial injury by impairing barrier integrity and promoting apoptosis. Targeting endothelial TRPV4 might represent a promising therapeutic strategy to mitigate myocardial IR injury.