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 microm, 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.