TY - JOUR
T1 - Deficiency of neuronal nitric oxide synthase increases mortality and cardiac remodeling after myocardial infarction
T2 - Role of nitroso-redox equilibrium
AU - Saraiva, Roberto M.
AU - Minhas, Khalid M.
AU - Raju, Shubha V.Y.
AU - Barouch, Lili A.
AU - Pitz, Eleanor
AU - Schuleri, Karl H.
AU - Vandegaer, Koenraad
AU - Li, Dechun
AU - Hare, Joshua M.
PY - 2005/11
Y1 - 2005/11
N2 - 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 β-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 β-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 β-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.
AB - 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 β-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 β-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 β-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.
KW - Heart failure
KW - Myocardial infarction
KW - Nitric oxide synthase
KW - Receptors, adrenergic, beta
UR - http://www.scopus.com/inward/record.url?scp=33644873609&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33644873609&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.105.557892
DO - 10.1161/CIRCULATIONAHA.105.557892
M3 - Article
C2 - 16301341
AN - SCOPUS:33644873609
SN - 0009-7322
VL - 112
SP - 3415
EP - 3422
JO - Circulation
JF - Circulation
IS - 22
ER -