Myocardial Ischemia/Reperfusion Injury in NADPH Oxidase–Deficient Mice

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Abstract
—Previous studies have suggested that oxygen-derived free radicals are involved in the pathophysiology of myocardial ischemia/reperfusion (MI/R) injury. Specifically, neutrophils have been shown to mediate postischemic ventricular arrhythmias and myocardial necrosis. We hypothesized that MI/R injury would be reduced in the absence (−/−) of NADPH oxidase. Heterozygous control mice (n=23) and NADPH oxidase–/– mice (n=24) were subjected to 30 minutes of coronary artery occlusion and 24 hours of reperfusion. Myocardial area at risk per left ventricle was similar in heterozygous control hearts (55±3%) and NADPH oxidase–/– hearts (61±4%). Contrary to our hypothesis, the size of infarct area at risk was similar in the heterozygous control mice (42±4%) and NADPH oxidase–/– mice (34±5%) (P=not significant). In addition, echocardiographic examination of both groups revealed that left ventricle fractional shortening was similar in NADPH oxidase–/– mice (n=8; 27±2.5%) and heterozygous control mice (n=10; 23.3±3.3%) after MI/R. Superoxide production, as detected by cytochrome c reduction, was significantly impaired (P–/– mice (n=6) compared with heterozygous mice (n=7) (0.04±0.03 versus 2.2±0.08 nmol O2·min–1·106 cells–1). Intravital microscopy of the inflamed mesenteric microcirculation demonstrated that leukocyte rolling and adhesion were unaffected by the absence of NADPH oxidase. Oyster glycogen-stimulated neutrophil transmigration into the peritoneum was also similar in both the heterozygous control mice and NADPH oxidase–/– mice (P=not significant). These findings suggest that NADPH oxidase does not contribute to the development of myocardial injury and dysfunction after MI/R.