RGD Reference Report - Inhibiting protease-activated receptor 4 limits myocardial ischemia/reperfusion injury in rat hearts by unmasking adenosine signaling. - Rat Genome Database

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Inhibiting protease-activated receptor 4 limits myocardial ischemia/reperfusion injury in rat hearts by unmasking adenosine signaling.

Authors: Strande, JL  Hsu, A  Su, J  Fu, X  Gross, GJ  Baker, JE 
Citation: Strande JL, etal., J Pharmacol Exp Ther. 2008 Mar;324(3):1045-54. Epub 2007 Nov 30.
RGD ID: 9835369
Pubmed: PMID:18055876   (View Abstract at PubMed)
PMCID: PMC2935083   (View Article at PubMed Central)
DOI: DOI:10.1124/jpet.107.133595   (Journal Full-text)

Harnessing endogenous cardioprotectants is a novel therapeutic strategy to combat ischemia/reperfusion (I/R) injury. Thrombin causes I/R injury, whereas exogenous adenosine prevents I/R injury. We hypothesized that blocking thrombin receptor activation with a protease-activated receptor (PAR) 4 antagonist would unmask the cardioprotective effects of endogenous adenosine. The protective role of two structurally unrelated PAR4 antagonists, trans-cinnamoyl-YPGKF-amide (tc-Y-NH(2)) and palmitoyl-SGRRYGHALR-amide (P4pal10), were evaluated in two rat models of myocardial I/R injury. P4pal10 (10 microg/kg) treatment before ischemia significantly decreased infarct size (IS) by 31, 21, and 19% when given before, during, and after ischemia in the in vivo model. tc-Y-NH(2) (5 microM) treatment before ischemia decreased IS by 51% in the in vitro model and increased recovery of ventricular function by 26%. To assess whether the cardioprotective effects of PAR4 blockade were due to endogenous adenosine, isolated hearts were treated with a nonselective adenosine receptor blocker, 8-sulfaphenyltheophylline (8-SPT), and tc-Y-NH(2) before ischemia. 8-SPT abolished the protective effects of tc-Y-NH(2) but did not affect IS when given alone. Adenosine-mediated survival pathways were then explored. The cardioprotective effects of tc-Y-NH(2) were abolished by inhibition of Akt (wortmannin), extracellular signal-regulated kinase 1/2 [PD98059 (2'-amino-3'-methoxyflavone)], nitric-oxide synthase [N(G)-monomethyl-l-arginine (l-NMA)], and K(ATP) channels (glibenclamide). PD98059, l-NMA, and glibenclamide alone had no effect on cardioprotection in vitro. Furthermore, inhibition of mitochondrial K(ATP) channels [5-hydroxydecanoic acid (5-HD)] and sarcolemmal K(ATP) channels (sodium (5-(2-(5-chloro-2-methoxybenzamido)ethyl)-2-methoxyphenylsulfonyl)(methylcarbamot hioyl)amide; HMR 1098) abolished P4pal10-induced cardioprotection in vivo. Thrombin receptor blockade by PAR4 inhibition provides protection against injury from myocardial I/R by unmasking adenosine receptor signaling and supports the hypothesis of a coupling between thrombin receptors and adenosine receptors.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Myocardial Reperfusion Injury treatmentISOPawr (Rattus norvegicus)9835369; 9835369 RGD 
Myocardial Reperfusion Injury treatmentIMP 9835369 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pawr  (pro-apoptotic WT1 regulator)

Genes (Mus musculus)
Pawr  (PRKC, apoptosis, WT1, regulator)

Genes (Homo sapiens)
PAWR  (pro-apoptotic WT1 regulator)


Additional Information