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CARDIOVASCULAR

Inhibiting Protease-Activated Receptor 4 Limits Myocardial Ischemia/Reperfusion Injury in Rat Hearts by Unmasking Adenosine Signaling

Divisions of Cardiovascular Medicine (J.L.S.) and Cardiothoracic Surgery (J.S., X.F., J.E.B.), Department of Pharmacology and Toxicology (A.H., G.J.G.), and Children's Research Institute (J.E.B.), Medical College of Wisconsin, Milwaukee, Wisconsin

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-NH₂) and palmitoyl-SGRRYGHALR-amide (P4pal10), were evaluated in two rat models of myocardial I/R injury. P4pal10 (10 µg/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-NH₂ (5 µM) 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-NH₂ before ischemia. 8-SPT abolished the protective effects of tc-Y-NH₂ but did not affect IS when given alone. Adenosine-mediated survival pathways were then explored. The cardioprotective effects of tc-Y-NH₂ 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.

Address correspondence to: Dr. Jennifer L. Strande, Division of Cardiovascular Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. E-mail: jstrande{at}mcw.edu

This article has been cited by other articles:

				J. L. Strande Letter by Strande Regarding Article "Protease-Activated Receptor-1 Contributes to Cardiac Remodeling and Hypertrophy" Circulation, June 17, 2008; 117(24): e495 - e495. [Full Text] [PDF]