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

Abstract

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 ␣ (TNF␣) 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 TNF␣ and PAR-2 are involved in signaling in pathophysiological conditions, such as myocardial ischemia-reperfusion. At the same time, because TNF␣ 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.

Protease-Activated Receptor-2 Activation

“…Although PAR 2 activation seems to be involved in leukocyte migration, inflammation of joints, skin, and kidney, and allergic inflammation of airways, 3 it has also been linked to some protective anti-inflammatory activities via the epithelium and vascular endothelium in the airways, 14 in the mucosal tissues of the gastrointestinal tract, 15 or in response to cardiovascular injury. 42 Conversely, the results from the present study clearly demonstrate that upon infection, PAR 2 plays a proinflammatory role in gingival tissues. Our data demonstrate that in the presence of P. gingivalis, PAR 2 activation leads to a significant increase in inflammatory cell infiltration, which was inhibited by SBTI and significantly reduced in PAR 2 -deficient (PAR 2 Ϫ/Ϫ ) mice.…”

Enzymatic Measurement of Tryptase-Like Protease Release from Isolated Perfused Guinea Pig Heart during Ischemia-Reperfusion

“…9) Furthermore, it has been reported that PAR-2-dependent signaling events are involved in heart protection by ischemic-preconditioning. 10) Since the highest levels of tryptase release were observed within 10 min of the onset of ischemia in this study, it is possible that tryptase is released during ischemic preconditioning usually caused by 5 min ischemia.…”

Effect of Protease-Activated Receptor-2 Deficiency on Allergic Dermatitis in the Mouse Ear

“…So far, many reports suggested detrimental effects of PAR-2 activation (11 -17), although PAR-2 activation also showed protective effects in myocardial ischemiareperfusion injury (18), airways (19,20) and cerebral circulation during chronic hypertension (21).…”