on November 21, 2005
Published online before print November 21, 2005, doi: 10.1161/CIRCULATIONAHA.105.557892
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Submitted on April 25, 2005
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. * To whom correspondence should be addressed. E-mail: jhare{at}mail.jhmi.edu.
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 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 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
Revised on September 15, 2005
Accepted on October 3, 2005
Deficiency of Neuronal Nitric Oxide Synthase Increases Mortality and Cardiac Remodeling After Myocardial Infarction. Role of Nitroso-Redox Equilibrium
Roberto M. Saraiva MD,
-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.-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.-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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