Original Contribution MYELOPEROXIDASE ENHANCES NITRIC OXIDE CATABOLISM DURING MYOCARDIAL ISCHEMIA AND REPERFUSION STEPHAN BALDUS,* THOMAS HEITZER,* JASON P. EISERICH, y DENISE LAU,* HANKE MOLLNAU, z MICHELLE ORTAK,* SUSAN PETRI, § BRITTA GOLDMANN,* HANS-JU ¨ RGEN DUCHSTEIN, O JU ¨ RGEN BERGER, b UDO HELMCHEN, § BRUCE A. FREEMAN,** THOMAS MEINERTZ,* and THOMAS MU ¨ NZEL z Departments of *Cardiology, § Pathology, and O Mathematics and Computer Science in Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany; y Department of Internal Medicine and Department of Human Physiology, University of California at Davis, Davis, CA, USA; z Department of Cardiology, University Hospital Mainz, Mainz, Germany; b Department of Pharmacy, University of Hamburg, Hamburg, Germany; and **Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL, USA (Received 12 May 2004; Revised 3 June 2004; Accepted 4 June 2004) Available online 2 July 2004 Abstract—Impaired microvascular function during myocardial ischemia and reperfusion is associated with recruitment of polymorphonuclear neutrophils (PMN) and has been attributed to decreased bioavailability of nitric oxide (NO). Whereas myeloperoxidase (MPO), a highly abundant, PMN-derived heme protein facilitates oxidative NO consumption and impairs vascular function in animal models of acute inflammation, its capacity to function in this regard during human myocardial ischemia and reperfusion remains unknown. Plasma samples from 30 consecutive patients (61 F 14 years, 80% male) presenting with acute myocardial infarction were collected 9 F 4 h after vessel recanalization and compared to plasma from healthy control subjects (n = 12). Plasma levels of MPO were higher in patients than in control subjects (1.4 F 0.9 vs 0.3 F 0.2 ng/mg protein, respectively, p < 0.0001). The addition of hydrogen peroxide to patient plasma resulted in accelerated rates of NO consumption compared to control subjects (0.53 F 0.25 vs 0.068 F 0.039 nM/ s/mg protein, respectively, p < 0.0001). Myocardial tissue from patients with the same pathology revealed intense recruitment of MPO-positive PMN localized along infarct-related vessels as well as diffuse endothelial distribution of non-PMN-associated MPO immunoreactivity. Endothelium-dependent microvascular function, as assessed by an acetylcholine-dependent increase in forearm blood flow in 75 patients with symptomatic coronary artery disease, inversely correlated with MPO plasma levels (r = 0.75, p < 0.005). Plasma from patients undergoing myocardial reperfusion contained increased levels of MPO, which catalytically consumed NO in the presence of H 2 O 2 . Given the correlation between intravascular MPO levels and forearm vasomotor function in patients with coronary artery disease, MPO appears to be an important modulator of vasomotor function in inflammatory vascular disease and a potential therapeutic target for treatment. D 2004 Elsevier Inc. All rights reserved. Keywords—Myocardial infarction, Myeloperoxidase, Hydrogen peroxide, Polymorphonuclear neutrophils, Reperfu- sion, Nitric oxide, Free radicals, Endothelial dysfunction INTRODUCTION Persistent myocardial ischemia caused by thrombotic oc- clusion at a ruptured or eroded coronary atherosclerotic plaque leads to irreversible myocyte cell death. Accord- ingly, reinstatement of coronary flow by thrombolysis or primary angioplasty reduces morbidity and mortality in patients with acute myocardial infarction. However, a large body of evidence indicates that reperfusion itself accounts for myocardial injury, extending from coronary no-reflow to myocardial stunning and myocyte necrosis [1]. Histologically, myocardial ischemia and reperfusion are characterized by an intense inflammatory reaction Address correspondence to: Dr. Stephan Baldus, University Hospital Hamburg-Eppendorf, Department of Cardiology, Martinistrasse 52, 20246 Hamburg, Germany; Fax: +49 40 42803 2967; E-mail: baldus@ uke.uni-hamburg.de. Free Radical Biology & Medicine, Vol. 37, No. 6, pp. 902 –911, 2004 Copyright D 2004 Elsevier Inc. Printed in the USA. All rights reserved 0891-5849/$-see front matter doi:10.1016/j.freeradbiomed.2004.06.003 902