Activation of Protease Activated Receptor-2 Induces Delayed Cardioprotection in Anesthetized Mice

To the Editor: Widespread expression of functional PAR2 in the cardiovascular system has led to the suggestion that PAR2 may play an important role in various cardiovascular pathophysiological conditions such as myocardial ischemia–reperfusion injury (MIRI) [1]. The recent publication by Jiang et al. [2] has reignited the interest of the cardioprotective effect of protease activated receptor-2 (PAR2) activation which was originally demonstrated by Napoli et al. in 2000 [3] and subsequently in 2002 [4]. The objective of this letter is to provide a confirmative in vivo finding in PAR2 deficient (PAR2) mice to support the cardioprotective effect of PAR2 activation demonstrated in rat model of MIRI [2, 3]. Using an anesthetized murine model of acute MIRI [5], we have shown that activation of PAR2 with the endogenous ligand, trypsin, or the synthetic activating peptide, SLIGRL-NH2 (SL-NH2) significantly reduced infarct size in PAR2 mice at 24 h postadministration (Fig. 1). The magnitude of the PAR2 mediated cardioprotection was similar to that of adenosine A1 receptor agonist, 2-chloro2-N -cyclopentyladenosine (CCPA), which is an established pharmacological preconditioning agent [6]. In PAR2 mice, the infarct sparing effect of trypsin and SL-NH2 was not seen, whereas the effect of the PAR2 independent agonist, CCPA, was maintained (Fig. 1). This data supports the conclusion that the cardioprotection afforded by PAR2 agonists is mediated via that receptor. Furthermore, this finding extends previous results by demonstrating that, in addition to the acute preconditioning [3] and postconditioning effects [2] of PAR2 agonists, PAR2 activation can induce delayed preconditioning. Interestingly, infarct size was not significantly modified by PAR2 deletion itself (Fig. 1) indicating that PAR2 did not play a role in the development of acute MIRI. The cardioprotective effect of PAR2 agonists has been demonstrated to be associated with the activation of protein kinase C and extra-cellular signal regulated kinase (ERK) 1/2 [2], increases in cardiac tissue TNFα levels and manganese superoxide dismutase activity [3, 4]. In a recent in vivo study examining the protective effect of SL-NH2 against intestinal injury caused by ischemia–reperfusion, it was shown that mast cell activation was involved in the underlying mechanism of protection [7]. PAR2 is expressed on cardiac mast cells and activation leads to mast cell degranulation and the release of various biologically active mediators including TNFα [8, 9]. Therefore, there is a possibility that PAR2 agonists could mimic ischemic preconditioning by inducing Cardiovasc Drugs Ther (2009) 23:519–520 DOI 10.1007/s10557-007-6073-8