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

Abstract

BackgroundThe transient receptor potential vanilloid 1 (TRPV1) mediates cellular responses to pain, heat, or noxious stimuli by calcium influx; however, the cellular localization and function of TRPV1 in the cardiomyocyte is largely unknown. We studied whether myocardial injury is regulated by TRPV1 and whether we could mitigate reperfusion injury by limiting the calcineurin interaction with TRPV1.Methods and ResultsIn primary cardiomyocytes, confocal and electron microscopy demonstrates that TRPV1 is localized to the mitochondria. Capsaicin, the specific TRPV1 agonist, dose‐dependently reduced mitochondrial membrane potential and was blocked by the TRPV1 antagonist capsazepine or the calcineurin inhibitor cyclosporine. Using in silico analysis, we discovered an interaction site for TRPV1 with calcineurin. We synthesized a peptide, V1‐cal, to inhibit the interaction between TRPV1 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 TRPV1 knockout rats.Conclusions TRPV1 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 TRPV1. These data suggest that TRPV1 is an end‐effector of cardioprotection and that modulating the TRPV1 protein interaction with calcineurin limits reperfusion injury.

Transient receptor potential vanilloid 1 inhibitors block laparotomy‐ and opioid‐induced infarct size reduction in rats

“…If cardiac protection was neuron mediated, the ability for ischaemic preconditioning to reduce myocardial infarct size should not be abolished in an isolated heart model. We and others recently identified that TRPV1 is present and functional within the cardiac myocyte (Andrei et al, ; Hurt et al, ). TRPV1 also modulates myocardial ischaemia‐reperfusion injury through the regulation of mitochondrial membrane potential (Hurt et al, ).…”

“…Capsaicin (CAP) cream (0.1%; CVS Pharmacy, Woonsocket, Rhode Island, USA) was administered on the abdomen. The doses of morphine and capsazepine were determined from previous studies using our rodent myocardial ischaemia‐reperfusion model (Gross et al, ; Small et al, ; Hurt et al, ).…”

“…Although initially discovered only in neurons, TRPV1 is broadly expressed in non‐neuronal tissues including those found in the kidney, lung, heart and brain. Furthermore, TRPV1 activation reduces ischaemia‐reperfusion injury for these organs (Ueda et al ., ; Muzzi et al ., ; Wang et al ., ; Hurt et al, ). Therefore, since TRPV1 is widely expressed and when activated limits ischaemia‐reperfusion injury, it is critical to identify whether inhibiting TRPV1 for pain relief may interfere with the agents or interventions physicians administer in the operating room which can decrease organ injury.…”

Multiple H+ sensors mediate the extracellular acidification-induced [Ca2+]i elevation in cultured rat ventricular cardiomyocytes

“…Although ASICs and TRPV1 are mainly found in the nervous system, both channels have also been reported to express in cardiovascular systems1617182324, however, there is no evidence for their distribution in the heart. Here, we first demonstrated the presence of the mRNAs and proteins of ASIC1, 2 and 3 in the cultured myocardiac cells.…”

“…It is a tetrameric membrane protein composing of four identical subunits, and each subunit contains six transmembrane regions to form a non-selective cation channel with high permeability to Ca 2+  14. Although TRPV1 is firstly identified in sensory neurons in 199715, it is also identified in other tissues, especially in the cardiovascular system, including vascular smooth muscle cells, vascular endothelial cells16, and the mitochondria of cardiomyocytes17. Activation of TRPV1 channel by capsaicin has been reported to improve endothelium - dependent vasorelaxation and prevent hypertension18, Myocardial reperfusion injury is also reported to be mitigated by limiting the interaction between TRPV1 and calcineurin17.…”