Protease-activated receptor-2 (PAR-2) is a member of seven transmembrane domain
G protein-coupled receptors activated by proteolytic 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 first time that PAR-2 activation protects 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
glutathione cycle (
glutathione 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 alpha (
TNFalpha) expression in both nuclear extracts and whole heart homogenates. The recovery of coronary flow was not reverted by L-
nitroarginine methylester, indicating a NO-independent pathway for this effect.
Genistein, a
tyrosine kinase inhibitor, 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
TNFalpha and PAR-2 are involved in signaling in pathophysiological conditions, such as
myocardial ischemia-reperfusion. At the same time, because
TNFalpha may exert pro-inflammatory actions and PAR-2 may constitute one of the first protective mechanisms that signals a primary inflammatory response, our data support the concept that this network may regulate body responses to tissue injury.