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(Circulation. 2005;112:3415-3422.)
© 2005 American Heart Association, Inc.

Heart Failure

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

Role of Nitroso-Redox Equilibrium

Roberto M. Saraiva, MD; Khalid M. Minhas, MD; Shubha V.Y. Raju, MD, MHS; Lili A. Barouch, MD; Eleanor Pitz; Karl H. Schuleri, MD; Koenraad Vandegaer, BS; Dechun Li, MD; Joshua M. Hare, MD

From the Cardiology Division (R.M.S., K.M.M., S.V.Y.R., L.A.B., E.P., K.H.S., K.V., J.M.H.), Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Md; UNIFESP (Federal University of Sao Paulo) (R.M.S.), Sao Paulo, Brazil; and the Department of Anesthesiology and Critical Care Medicine (D.L.), Johns Hopkins Medical Institutions, Baltimore, Md.

Correspondence to Joshua M. Hare, MD, Johns Hopkins Medical Institutions, Cardiology Division and Institute for Cell Engineering, Broadway Research Building, 733 N Broadway, Suite 651, Baltimore, MD 21205. E-mail jhare{at}mail.jhmi.edu

Received April 25, 2005; revision received September 15, 2005; accepted October 3, 2005.

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 ß-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 ß-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 ß-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.

Key Words: myocardial infarction • nitric oxide synthase • heart failure • receptors, adrenergic, beta

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