Abstract 951: Protease-Activated Receptor 2-Mediated Protection of Myocardial Ischemia-Reperfusion Injury: Role of Transient Receptor Potential Vanilloid Receptors
Activation of protease-activated receptor (PAR) 2 has been proposed to play a protective role in myocardial ischemia/reperfusion (I/R) injury, however, the mechanism(s) underlying PAR2 action is largely unknown. This study was designed to test the novel hypothesis that the transient receptor potential vanilloid receptor 1 (TRPV1) plays a role in mediating PAR2-induced cardiac protective effects. Hearts from gene-targeted TRPV1-null mutant (TRPV1−/−) or wild-type (WT) mice were Langendorffly perfused in the presence or absence of receptor antagonists of TRPV1 or sensory neuropeptides prior to the administration of PAR2 activating peptide, SLIGRL, followed by 30 mins of global ischemia and 40 mins of reperfusion. Hemodynamic parameters, including left ventricular developed pressure (LVDP), end-diastolic pressure (EDP) , coronary flow (CF) rate, and maximal rate of pressure development (+dp/dt), were evaluated. After SLIGRL treatment, the cardiac protective effects defined by an increase in LVDP, CF, or +dp/dt and a decrease in EDP were significantly greater in WT than in TRPV1−/− hearts (p<0.05). Capsazepine (CAPZ), a selective TRPV1 antagonist; CGRP8–37, a selective calcitonin gene-related peptide (CGRP) receptor antagonist; RP67580, a selective NK1 receptor antagonist; or calphostin C, a selective protein kinase C receptor antagonist, significantly attenuated cardiac protective effects of SLIGRL in WT hearts (p<0.05). Radioimmunoassay showed that the release of CGRP and substance P induced by SLIGRL was significantly higher in WT than in TRPV1−/− hearts (p<0.05), which was attenuated by CAPZ in WT but not in TRPV1−/− hearts. Taken together, our data show that the cardiac protective effect of PAR2 is impaired in TRPV1−/− hearts or in WT hearts when TRPV1 is blocked, indicating that TRPV1 plays a key role in mediating the PAR2 beneficial action. Moreover, TRPV1 mediated effects of PAR2 involve TRPV1-dependent CGRP and SP release and PKC activation, which serve as down stream signaling pathways of PAR2-induced TRPV1 activation to protect hearts from ischemia/ reperfusion injury.