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

Carl M. Hurt, Yao Lu, Creed M. Stary, Honit Piplani, Bryce A. Small, Travis J. Urban, Nir Qvit, Garrett J. Gross, Daria Mochly-Rosen, Eric R. Gross

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Background: The 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 Results: In 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.

Original languageEnglish
Article numbere003774
JournalJournal of the American Heart Association
Volume5
Issue number9
DOIs
StatePublished - 26 Sep 2016
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Keywords

  • Acute myocardial infarction
  • Calcineurin
  • Cyclosporine
  • Infarct size
  • Ischemia
  • Mitochondria
  • Reperfusion
  • Reperfusion injury
  • Transient receptor potential vanilloid 1

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