Deficiency of neuronal nitric oxide synthase increases mortality and cardiac remodeling after myocardial infarction - Role of nitroso-redox equilibrium

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 beta- 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 mu m, P < 0.01), and equivalent beta- 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 beta- 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.