Deficiency of neuronal nitric oxide synthase increases mortality and cardiac remodeling after myocardial infarction: Role of nitroso-redox equilibrium

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

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish
Pages (from-to)3415-3422
Number of pages8
JournalCirculation
Volume112
Issue number22
DOIs
StatePublished - Nov 1 2005
Externally publishedYes

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Nitric Oxide Synthase Type I
Oxidation-Reduction
Myocardial Infarction
Mortality
Adrenergic Agents
Oxidative Stress
Xanthine Dehydrogenase
Excitation Contraction Coupling
Wild Animals
NADPH Oxidase
Sarcoplasmic Reticulum
Left Ventricular Dysfunction
Superoxides
Up-Regulation
Antioxidants
Cell Membrane
Wounds and Injuries

Keywords

  • Heart failure
  • Myocardial infarction
  • Nitric oxide synthase
  • Receptors, adrenergic, beta

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Deficiency of neuronal nitric oxide synthase increases mortality and cardiac remodeling after myocardial infarction : Role of nitroso-redox equilibrium. / Saraiva, Roberto M.; Minhas, Khalid M.; Raju, Shubha V Y; Barouch, Lili A.; Pitz, Eleanor; Schuleri, Karl H.; Vandegaer, Koenraad; Li, Dechun; Hare, Joshua.

In: Circulation, Vol. 112, No. 22, 01.11.2005, p. 3415-3422.

Research output: Contribution to journalArticle

Saraiva, Roberto M. ; Minhas, Khalid M. ; Raju, Shubha V Y ; Barouch, Lili A. ; Pitz, Eleanor ; Schuleri, Karl H. ; Vandegaer, Koenraad ; Li, Dechun ; Hare, Joshua. / Deficiency of neuronal nitric oxide synthase increases mortality and cardiac remodeling after myocardial infarction : Role of nitroso-redox equilibrium. In: Circulation. 2005 ; Vol. 112, No. 22. pp. 3415-3422.
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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 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.",
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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

PY - 2005/11/1

Y1 - 2005/11/1

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.

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