PR-39, a proline/arginine-rich antimicrobial peptide, exerts cardioprotective effects in myocardial ischemia-reperfusion

Objective: PR-39, a proline/arginine-rich antimicrobial peptide, has been shown to inhibit the NADPH oxidase activity of polymorphonuclear leukocytes (PMNs) by blocking assembly of this enzyme. We hypothesized that PR-39 could attenuate PMN-induced cardiac dysfunction by suppression of superoxide production. Methods: We examined the effects of PR-39 in isolated ischemic (20 min) and reperfused (45 min) rat hearts administered PMNs at the onset of reperfusion. Results: PR-39 (4 or 10 mug/ml) given i.v. 30 min prior to ischemia-reperfusion (I-R) significantly improved left ventricular developed pressure (LVDP, P<0.01) and the maximal rate of development of LVDP (i.e. +dP/dt max, P<0.01) compared to I-R hearts obtained from rats given 0.9% NaCl. PR-39-treated PMNs (10 mug/ml) also significantly attenuated cardiac contractile dysfunction after I-R (P<0.01). Superoxide release was significantly reduced (P<0.01) in N-formylmethionyl-leucylphenylalanine stimulated PMNs pretreated with 4 or 10 mug/ml PR-39. PR-39 also significantly attenuated P-selectin expression on the rat coronary microvascular endothelium and CD18 upregulation in rat PMNs. In addition, PR-39 significantly reduced PMN vascular adherence and infiltration into the post-ischemic myocardium. Conclusion: These results provide evidence that PR-39 significantly attenuates PMN-induced cardiac contractile dysfunction in the I-R rat heart at least in part via suppression of superoxide release. This cardioprotection occurred both by inhibition of PMN and endothelial NADPH oxidase. (C) 2001 Elsevier Science B.V. All rights reserved.