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



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.



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.
Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA.
Carl M
CM
Hurt
Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA.
Yao
Y
Lu
Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA.
Creed M
CM
Stary
Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA.
Honit
H
Piplani
Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA.
Bryce A
BA
Small
Department of Chemical and Systems Biology, School of Medicine, Stanford University, Stanford, CA.
Travis J
TJ
Urban
Department of Chemical and Systems Biology, School of Medicine, Stanford University, Stanford, CA.
Nir
N
Qvit
Department of Pharmacology, Medical College of Wisconsin, Milwaukee, WI.
Garrett J
GJ
Gross
Department of Chemical and Systems Biology, School of Medicine, Stanford University, Stanford, CA.
Daria
D
Mochly-Rosen
Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA ergross@stanford.edu.
Eric R
ER
Gross
acute myocardial infarction; calcineurin; cyclosporine; infarct size; ischemia; mitochondria; reperfusion; reperfusion injury; transient receptor potential vanilloid 1
Basic Res Cardiol. 2013 Sep;108(5):381
23982492
Nat Chem Biol. 2011 Aug 28;7(10 ):701-11
21873995
J Pharmacol Exp Ther. 2004 Jul;310(1):185-91
14993258
Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13522-6
12357034
Nat Struct Mol Biol. 2012 Feb 19;19(3):337-45
22343722
Int J Cardiol. 2009 May 15;134(2):290-2
18378339
Hypertension. 2009 Feb;53(2):243-50
19114647
J Biol Chem. 2006 Mar 31;281(13):8991-5
16431906
Anesthesiology. 2014 Aug;121(2):232-8
25050491
Circulation. 2004 Apr 13;109(14):1714-7
15066952
Heart. 2014 Apr;100(7):544-9
24488610
Am J Physiol Heart Circ Physiol. 2006 Jul;291(1):H344-50
16501018
Anesthesiology. 1997 Aug;87(2):361-70
9286901
J Neurochem. 2012 Nov;123(4):589-601
22891703
N Engl J Med. 2015 Sep 10;373(11):1021-31
26321103
J Membr Biol. 2009 Oct;231(2-3):79-92
19865787
N Engl J Med. 2008 Jul 31;359(5):473-81
18669426
J Cardiovasc Pharmacol. 2006 May;47(5):650-5
16775503
Pain. 2008 May;136(1-2):202-10
18337008
Nat Neurosci. 2002 Jun;5(6):546-51
11992116
Mol Cell Biol. 2011 Mar;31(6):1309-28
21245373
Biomed Res Int. 2015 ;2015 :129612
26413502
J Neurochem. 2006 Nov;99(4):1088-102
17018028
Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12784-9
10536000
Int J Emerg Med. 2012 Jan 20;5:5
22264348
Nature. 2013 Dec 5;504(7478):113-8
24305161
FASEB J. 2007 Sep;21(11):2695-703
17470568
J Am Heart Assoc. 2013 Oct 08;2(5):e000461
24103571
Wien Klin Wochenschr. 2012 Apr;124(7-8):285-7
22527825
J Neurosci. 1999 Jan 15;19(2):529-38
9880573
Nature. 2013 Dec 5;504(7478):107-12
24305160
J Gen Physiol. 2004 Jan;123(1):53-62
14699077
Anesth Analg. 2009 Nov;109 (5):1395-402
19843777
Eur J Biochem. 2001 Nov;268(21):5489-96
11683872
J Biol Chem. 2013 Jun 28;288(26):18947-60
23653351
Circulation. 2005 Jan 4;111(1):44-50
15611364
Cardiovasc Drugs Ther. 2014 Aug;28(4):295-301
24839185
Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1791-8
17586621
Circ Res. 2014 Aug 29;115(6):567-80
25047165
N Engl J Med. 2007 Sep 13;357(11):1121-35
17855673
Nature. 2007 Oct 4;449(7162):607-10
17914397
Biochem J. 2010 Dec 15;432(3):549-56
20883208
Mol Pharmacol. 2008 Nov;74(5):1261-8
18689441
J Neurosci. 2003 May 15;23 (10 ):4054-65
12764092
Am J Physiol Renal Physiol. 2006 Jan;290(1):F117-26
16091583
J Mol Biol. 2007 Jun 22;369(5):1296-306
17498738
Nature. 1997 Oct 23;389(6653):816-24
9349813
J Biol Chem. 2004 Feb 20;279(8):7048-54
14630912
Circ Res. 2004 Apr 16;94(7):960-6
14976126