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1 Hypertension &Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan, USA
2 Department of Biostatistics and Research Epidemiology, Henry Ford Hospital, Detroit, Michigan, USA
* To whom correspondence should be addressed. E-mail: xpyang1{at}hfhs.org.
Using iNOS knockout mice (iNOS-/-), we tested the hypotheses that 1) lack of iNOS attenuates cardiac remodeling and dysfunction and improves cardiac reserve post-myocardial infarction (MI), an effect that is partially mediated by reduction of oxidative stress due to reduced interaction between NO and reactive oxygen species (ROS); and 2) the cardioprotection afforded by iNOS deletion is eliminated by L-NAME due to inhibition of eNOS and nNOS. MI was induced by ligating the left anterior descending coronary artery. Male iNOS-/- mice and wild-type controls (WT, C57BL/6J) were divided into 1) sham MI; 2) MI + vehicle; and 3) MI + L-NAME (100 mg/kg/day in drinking water for 8 weeks). Cardiac function was evaluated by echocardiography. Left ventricular (LV) maximum dP/dt over instant pressure (dP/dt/iP) in response to isoproterenol (ISO; 100 ng/kg/min, i.v.) was measured with a Millar catheter. Collagen deposition, myocyte cross-sectional area and expression of nitrotyrosine and 4-hydroxy-2-nonenal (4-HNE), markers for reactive oxygen species, were determined by histopathological and immunohistochemical staining. We found that the MI-induced increase in LV chamber dimension and decrease in ejection fraction (EF), an index of systolic function, were less severe in iNOS-/- compared to WT. L-NAME worsened LV remodeling and dysfunction further, and these detrimental effects were also attenuated in iNOS-/- mice, associated with better preservation of cardiac function. Lack of iNOS also reduced nitrotyrosine and 4-HNE expression after MI, indicating reduced oxidative stress. We conclude that iNOS does not seem to be a pathological mediator of heart failure; however, lack of iNOS improves cardiac reserve post-MI, particularly when constitutive NOS isoforms are blocked. Decreased oxidative stress and other adaptive mechanisms independent of NOS may be partially responsible for such an effect, which needs to be studied further.
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