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

摘要

Protease-activated receptor-2 (PAR-2) is a member of seven trans- membrane domain G protein-coupled receptors adivated by proteo- lytic cleavage whose better 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 experimental myocardial ischemia-reperfusion injury. We show for the fist time that PAR-2 activation proteds against reperfusion-injury. After PAR-2-activating peptide (2AP) infusion. we found a significant recovery of myocardial function and decrease in oxidation at reflow. Indeed, the glutethione Cycle (glutathiohe and oxidized glutathione) and lipid peroxidation analysis showed a reduced oxidative reperfusion-injury. Moreover, ischemic risk zone and creatine kinase release were decreased after PAR-2AP treatment. These events were coupled to elevation of PAR-2 and tumor necrosis factor α(tNF)α expression in both nuclear extracts and whole heart homogenates. The recovery of coronary flow was not reverted by L-nitroarginine mothylester, indicating a NO-inde- pendent pathway for this effect. Genistein, a tyrosine kinase inhibi- tor, did not revert the PAR-2AP effect. During early reperfusion injury in vivo not only oxygen radicals are produced but also numerous proinflammatory mediators promoting neutrophil and monocyte targeting. In this context, we show that TNFα and PAR-2 are invoved in signaling in pathophysiological conditions, such as myocardial ischemia-reperfusion. At the same time, because TNFα may exert pro-inflammatory actions and PAR-2 may constitute one of the first prot6dive mechanisms that signals a primary inflammatory response. our data support the concept that this network may regulate body responses to tissue injury.