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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 30, 2007; DOI: 10.1124/jpet.107.133595

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Received for publication October 26, 2007.
Revised November 29, 2007.
Accepted for publication November 29, 2007.

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

Jennifer L. Strande 1*, Anna Hsu 1, Jidong Su 1, Xiangping Fu 1, Garrett J. Gross 1, John E. Baker 1

1 Medical College of Wisconsin

* Address correspondence to: E-mail: jstrande{at}mcw.edu

Abstract

Harnessing endogenous cardioprotectants is a novel therapeutic strategy to combat ischemia/reperfusion (I/R) injury. Thrombin causes whereas exogenous adenosine prevents I/R injury. We hypothesized that blocking thrombin receptor activation with a Protease-Activated Receptor 4 (PAR4) antagonist would unmask the cardioprotective effects of endogenous adenosine. The protective role of two structurally unrelated PAR4 antagonists, tc-Y-NH2 and 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 if the cardioprotective effects of PAR4 blockade were due to endogenous adenosine, isolated hearts were treated with a non-selective adenosine receptor blocker (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), ERK1/2 (PD98059), NOS (L-NMA) and KATP channels (glibenclamide). PD98059, L-NMA and glibenclamide alone had no effect on cardioprotection in vitro. Furthermore, inhibition of mitochondrial KATP channels (5-HD) and sarcolemmal KATP channels (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.


Key words: Adenosine, Ischemia, Myocardium, Protease-Activated Receptors, Reperfusion Injury, Thrombin Receptor Antagonist


This article has been cited by other articles:


Home page
 CirculationHome page
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.
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