Abstract 553: In Vivo Cardioprotection by Postconditioning is Mediated by Endogenous PAR2 Activation

Abstract

Background : Protease activated receptor 2 (PAR2) is a member of the seven transmembrane G-protein coupled receptor (GPCR) family. Activation of PAR2 is cardioprotective in ex vivo and in vivo myocardial ischemia reperfusion model, potentially by cognate ligands released at reperfusion (R). Postconditioning (postcon), defined as alternating brief (seconds) episodes of R and ischemia applied at the onset of R , is also cardioprotective. This cardioprotection involves activation of GPCR by adenosine, bradykinin and opioids. However, the role of the GPCR PAR2 in cardioprotection by postcon has not been investigated. Hypothesis : This study tested the hypothesis that cardioprotection by postcon is mediated in part by endogenous PAR2 activation. Methods : Rats were randomly assigned to one of 5 groups with 30 min left coronary artery (LCA) occlusion followed by 3 h reperfusion: Control: no intervention was applied either before or after LCA occlusion (n =8); Postcon alone: 3 cycles of 10-s full reperfusion and 10-s re-occlusion were initiated at the onset of R (n=8); PAR2 antagonist alone: the selective PAR2 antagonist (FSLLRY-NH2, 1 mg/Kg) was injected 5 min before R (n=8); PAR2 antagonist + Postcon: PAR2 antagonist (1 mg/Kg) was administered 5 min before Postcon (n=8); Delayed PAR2 antagonist: PAR2 antagonist (1 mg/Kg) was given 5 min after the postcon protocol (n=8). Results: Area at risk (AAR) was comparable in all groups (35–38%). Compared to control, infarct size (TTC, area of necrosis/AAR, %) was significantly reduced by postcon alone (39.0% ± 1.3% vs 53.7% ± 1.5%, P<0.05). The PAR2 antagonist alone administered just before R had no effect on infarct size (57.4% ± 2.4% vs 53.7% ± 1.5%). Interestingly, the infarct sparing effect of postcon was completely reversed by PAR2 antagonist administered before postcon to control values ( 56.7% ± 2.7% *). Furthermore, the infarct sparing effect of postcon was also blocked by PAR2 antagonist given after postcon (50.3% ± 3.3% *). These results suggest that endogenous PAR2 activation induced by postcon during the early moments of R is cardioprotective. Conclusions : Cardioprotection by postcon is mediated, in part, by activation of endogenous PAR2, and suggests a general activation of GPCR. *P<0.05 vs Postcon.