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

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 anta...

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Published in:	The Journal of pharmacology and experimental therapeutics 2008-03, Vol.324 (3), p.1045-1054
Main Authors:	Strande, Jennifer L, Hsu, Anna, Su, Jidong, Fu, Xiangping, Gross, Garrett J, Baker, John E
Format:	Article
Language:	eng
Subjects:	Adenosine - metabolism Animals Cardiotonic Agents - pharmacology Cardiotonic Agents - therapeutic use Heart - drug effects Heart - physiology Male Myocardial Reperfusion Injury - metabolism Myocardial Reperfusion Injury - prevention & control Rats Rats, Sprague-Dawley Receptors, Thrombin - antagonists & inhibitors Receptors, Thrombin - metabolism Signal Transduction - drug effects Signal Transduction - physiology
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Summary:	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 Î¼g/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 Î¼M) 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 (2â²-amino-3â²-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.
ISSN:	0022-3565 1521-0103