Transient Receptor Potential Vanilloid 1 Regulates Mitochondrial Membrane Potential and Myocardial Reperfusion Injury

Abstract

Background The transient receptor potential vanilloid 1 ( TRPV 1) mediates cellular responses to pain, heat, or noxious stimuli by calcium influx; however, the cellular localization and function of TRPV 1 in the cardiomyocyte is largely unknown. We studied whether myocardial injury is regulated by TRPV 1 and whether we could mitigate reperfusion injury by limiting the calcineurin interaction with TRPV 1. Methods and Results In primary cardiomyocytes, confocal and electron microscopy demonstrates that TRPV 1 is localized to the mitochondria. Capsaicin, the specific TRPV 1 agonist, dose‐dependently reduced mitochondrial membrane potential and was blocked by the TRPV 1 antagonist capsazepine or the calcineurin inhibitor cyclosporine. Using in silico analysis, we discovered an interaction site for TRPV 1 with calcineurin. We synthesized a peptide, V1‐cal, to inhibit the interaction between TRPV 1 and calcineurin. In an in vivo rat myocardial infarction model, V1‐cal given just prior to reperfusion substantially mitigated myocardial infarct size compared with vehicle, capsaicin, or cyclosporine (24±3% versus 61±2%, 45±1%, and 49±2%, respectively; n=6 per group; P <0.01 versus all groups). Infarct size reduction by V1‐cal was also not seen in TRPV 1 knockout rats. Conclusions TRPV 1 is localized at the mitochondria in cardiomyocytes and regulates mitochondrial membrane potential through an interaction with calcineurin. We developed a novel therapeutic, V1‐cal, that substantially reduces reperfusion injury by inhibiting the interaction of calcineurin with TRPV 1. These data suggest that TRPV 1 is an end‐effector of cardioprotection and that modulating the TRPV 1 protein interaction with calcineurin limits reperfusion injury.