RGD Reference Report - Transient Receptor Potential Vanilloid 1 Regulates Mitochondrial Membrane Potential and Myocardial Reperfusion Injury. - Rat Genome Database

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

Authors: Hurt, Carl M  Lu, Yao  Stary, Creed M  Piplani, Honit  Small, Bryce A  Urban, Travis J  Qvit, Nir  Gross, Garrett J  Mochly-Rosen, Daria  Gross, Eric R 
Citation: Hurt CM, etal., J Am Heart Assoc. 2016 Sep 26;5(9). pii: JAHA.116.003774. doi: 10.1161/JAHA.116.003774.
RGD ID: 13792689
Pubmed: PMID:27671317   (View Abstract at PubMed)
PMCID: PMC5079036   (View Article at PubMed Central)
DOI: DOI:10.1161/JAHA.116.003774   (Journal Full-text)


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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
myocardial infarction  IMP 13792689; 13792689; 13792689 RGD 
myocardial infarction  ISOTrpv1 (Rattus norvegicus)13792689; 13792689 RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
negative regulation of mitochondrial membrane potential  IMP 13792689 RGD 


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Objects Annotated

Genes (Rattus norvegicus)
Trpv1  (transient receptor potential cation channel, subfamily V, member 1)
Trpv1em1Sage  (transient receptor potential cation channel, subfamily V, member 1; ZFN induced mutant 1, Sage)

Genes (Mus musculus)
Trpv1  (transient receptor potential cation channel, subfamily V, member 1)

Genes (Homo sapiens)
TRPV1  (transient receptor potential cation channel subfamily V member 1)

Strains
SD-Trpv1em1Sage-/-  (NA)

Objects referenced in this article
Strain SD-Trpv1em1Sage+/+ null Rattus norvegicus

Additional Information