title: Deficiency of neuronal nitric oxide synthase increases mortality and cardiac remodeling after myocardial infarction: role of nitroso-redox equilibrium.
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 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.
  
  
  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.
authors.affiliation: Cardiology Division, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
authors.forename: Roberto M
authors.initials: RM
authors.lastname: Saraiva
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Minhas
authors.forename: Shubha V Y
authors.initials: SV
authors.lastname: Raju
authors.forename: Lili A
authors.initials: LA
authors.lastname: Barouch
authors.forename: Eleanor
authors.initials: E
authors.lastname: Pitz
authors.forename: Karl H
authors.initials: KH
authors.lastname: Schuleri
authors.forename: Koenraad
authors.initials: K
authors.lastname: Vandegaer
authors.forename: Dechun
authors.initials: D
authors.lastname: Li
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000209:etiology / Q000401:mortality; D006706:Homeostasis; D051379:Mice; D018345:Mice, Knockout; D009026:Mortality; D009203:Myocardial Infarction / Q000150:complications* / Q000401:mortality*; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency* / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D013481:Superoxides / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000209:etiology
chemical_list: D013481:Superoxides; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D019255:NADPH Oxidases