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

doi:10.1016/S0008-6363(00)00226-1

Cardiovascular Research 2001 49(1):69-77; doi:10.1016/S0008-6363(00)00226-1
© 2001 by European Society of Cardiology

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

Yasuhiko Ikeda¹^,a, Lindon H Young²^,a, Rosario Scalia^a, Christopher R Ross^b and Allan M Lefer^a^,*

^aDepartment of Physiology, Jefferson Medical College, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107-6799, USA
^bDepartment of Anatomy and Physiology, Kansas State University, Manhattan, KS 66506, USA

^* Corresponding author. Tel.: +1-215-503-7760; fax: +1-215-503-2073 allan.m.lefer{at}mail.tju.edu

Objective: PR-39, a proline/arginine-rich antimicrobial peptide,has been shown to inhibit the NADPH oxidase activity of polymorphonuclearleukocytes (PMNs) by blocking assembly of this enzyme. We hypothesizedthat PR-39 could attenuate PMN-induced cardiac dysfunction bysuppression of superoxide production. Methods: We examined theeffects 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 µg/ml) given i.v. 30 min priorto ischemia–reperfusion (I–R) significantly improvedleft ventricular developed pressure (LVDP, P<0.01) and themaximal 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 µg/ml) also significantly attenuatedcardiac contractile dysfunction after I–R (P<0.01).Superoxide release was significantly reduced (P<0.01) inN-formylmethionyl-leucylphenylalanine stimulated PMNs pretreatedwith 4 or 10 µg/ml PR-39. PR-39 also significantly attenuatedP-selectin expression on the rat coronary microvascular endotheliumand CD18 upregulation in rat PMNs. In addition, PR-39 significantlyreduced PMN vascular adherence and infiltration into the post-ischemicmyocardium. Conclusion: These results provide evidence thatPR-39 significantly attenuates PMN-induced cardiac contractiledysfunction in the I–R rat heart at least in part viasuppression of superoxide release. This cardioprotection occurredboth by inhibition of PMN and endothelial NADPH oxidase.

KEYWORDS Coronary circulation; Coronary disease; Endothelial function; Leukocytes; Reperfusion

¹ Y.I. is a Research Fellow of the Japanese Society of ClinicalPharmacology and Therapeutics.

² L.H.Y. is a Postdoctoral Trainee of the National Heart, Lungand Blood Institute of the NIH (HL-07599).

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