Inhibiting protease-activated receptor 4 limits myocardial ischemia/reperfusion injury in rat hearts by unmasking adenosine signaling. J Pharmacol Exp Ther 2008 Mar;324(3):1045-54
Date
12/07/2007Pubmed ID
18055876Pubmed Central ID
PMC2935083DOI
10.1124/jpet.107.133595Scopus ID
2-s2.0-40849113307 (requires institutional sign-in at Scopus site) 47 CitationsAbstract
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)(methylcarbamothioyl)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.
Author List
Strande JL, Hsu A, Su J, Fu X, Gross GJ, Baker JEAuthor
John E. Baker PhD Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdenosineAnimals
Cardiotonic Agents
Heart
Male
Myocardial Reperfusion Injury
Rats
Rats, Sprague-Dawley
Receptors, Thrombin
Signal Transduction