Protease-activated receptor-2 modulates myocardial ischemia-reperfusion injury in the rat heart

Protease-activated receptor-2 (PAR-2) is a member of seven transmembrane do main G protein-coupled receptors activated by proteolytic cleavage whose be tter known member is the thrombin receptor. The pathophysiological role of PAR-2 remains poorly understood. Because PAR-2 is involved in inflammatory and injury response events, we investigated the role of PAR-2 in experiment al myocardial ischemia-reperfusion injury. We show for the first time that PAR-2 activation protects against reperfusion-injury. After PAR-2-activatin g peptide (2AP) infusion, we found a significant recovery of myocardial fun ction and decrease in oxidation at reflow. Indeed, the glutathione cycle (g lutathione and oxidized glutathione) and lipid peroxidation analysis showed a reduced oxidative reperfusion-injury. Moreover, ischemic risk zone and c reatine kinase release were decreased after PAR-2AP treatment These events were coupled to elevation of PAR-2 and tumor necrosis factor alpha (TNF alp ha) expression in both nuclear extracts and whole heart homogenates. The re covery of coronary flow was not reverted by L-nitroarginine methylester, in dicating a NO-independent pathway for this effect Genistein, a tyrosine kin ase inhibitor, did not revert the PAR-2AP effect. During early reperfusion injury in vivo not only oxygen radicals are produced but also numerous proi nflammatory mediators promoting neutrophil and monocyte targeting, in this context we show that TNF alpha and PAR-2 are involved in signaling in patho physiological conditions, such as myocardial ischemia-reperfusion. At the s ame time, because TNF alpha may exert pro-inflammatory actions and PAR-2 ma y constitute one of the first protective mechanisms that signals a primary inflammatory response, our data support the concept that this network may r egulate body responses to tissue injury.