Deficiency of Neuronal Nitric Oxide Synthase Increases Mortality and Cardiac Remodeling After Myocardial Infarction

Abstract

Background— Neuronal nitric oxide synthase (NOS1) plays key cardiac physiological roles, regulating excitation-contraction coupling and exerting an antioxidant effect that maintains tissue NO-redox equilibrium. After myocardial infarction (MI), NOS1 translocates from the sarcoplasmic reticulum to the cell membrane, where it inhibits β-adrenergic contractility, an effect previously predicted to have adverse consequences. Counter to this idea, we tested the hypothesis that NOS1 has a protective effect after MI. Methods and Results— We studied mortality, cardiac remodeling, and upregulation of oxidative stress pathways after MI in NOS1-deficient (NOS1 −/− ) and wild-type C57BL6 (WT) mice. Compared with WT, NOS1 −/− mice had greater mortality (hazard ratio, 2.06; P =0.036), worse left ventricular (LV) fractional shortening (19.7±1.5% versus 27.2±1.5%, P <0.05), higher LV diastolic diameter (5.5±0.2 versus 4.9±0.1 mm, P <0.05), greater residual cellular width (14.9±0.5 versus 12.8±0.5 μm, P <0.01), and equivalent β-adrenergic hyporesponsiveness despite similar MI size. Superoxide production increased after MI in both NOS1 −/− and WT animals, although NO increased only in WT. NADPH oxidase ( P <0.05) activity increased transiently in both groups after MI, but NOS1 −/− mice had persistent basal and post-MI elevations in xanthine oxidoreductase activity. Conclusions— Together these findings support a protective role for intact NOS1 activity in the heart after MI, despite a potential contribution to LV dysfunction through β-adrenergic hyporesponsiveness. NOS1 deficiency contributes to an imbalance between oxidative stress and tissue NO signaling, providing a plausible mechanism for adverse consequences of NOS1 deficiency in states of myocardial injury.