Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction

Yun He Liu, Oscar A. Carretero, Oscar Cingolani, Tang Dong Liao, Ying Sun, Jiang Xu, Lisa Y. Li, Patrick J. Pagano, James J. Yang, Xiao Ping Yang

Research output: Contribution to journalArticle

Abstract

Using inducible nitric oxide (NO) synthase (iNOS) knockout mice (iNOS -/-), we tested the hypotheses that 1) lack of iNOS attenuates cardiac remodeling and dysfunction and improves cardiac reserve postmyocardial infarction (MI), an effect that is partially mediated by reduction of oxidative stress due to reduced interaction between NO and reactive oxygen species (ROS); and 2) the cardioprotection afforded by iNOS deletion is eliminated by N ω-nitro-L-arginine methyl ester (L-NAME) due to inhibition of endothelial NOS (eNOS) and neuronal NOS (nNOS). MI was induced by ligating the left anterior descending coronary artery. Male iNOS-/- mice and wild-type controls (WT, C57BL/6J) were divided into sham MI, MI+vehicle, and MI+L-NAME (100 mg·kg-1·day-1 in drinking water for 8 wk). Cardiac function was evaluated by echocardiography. Left ventricular (LV) maximum rate of rise of ventricular pressure divided by pressure at the moment such maximum occurs (dP/dt/instant pressure) in response to isoproterenol (100 ng·kg-1·min-1 iv) was measured with a Millar catheter. Collagen deposition, myocyte cross-sectional area, and expression of nitrotyrosine and 4-hydroxy-2-nonenal (4-HNE), markers for ROS, were determined by histopathological and immunohistochemical staining. We found that the MI-induced increase in LV chamber dimension and the decrease in ejection fraction, an index of systolic function, were less severe in iNOS-/- compared with WT mice. L-NAME worsened LV remodeling and dysfunction further, and these detrimental effects were also attenuated in iNOS-/- mice, associated with better preservation of cardiac function. Lack of iNOS also reduced nitrotyrosine and 4-HNE expression after MI, indicating reduced oxidative stress. We conclude that iNOS does not seem to be a pathological mediator of heart failure; however, the lack of iNOS improves cardiac reserve post-MI, particularly when constitutive NOS isoforms are blocked. Decreased oxidative stress and other adaptive mechanisms independent of NOS may be partially responsible for such an effect, which needs to be studied further.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume289
Issue number6 58-6
DOIs
StatePublished - Dec 2005
Externally publishedYes

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NG-Nitroarginine Methyl Ester
Nitric Oxide Synthase Type II
Oxidative Stress
Heart Failure
Myocardial Infarction
Reactive Oxygen Species
Pressure
Ventricular Remodeling
Left Ventricular Dysfunction
Ventricular Pressure
Isoproterenol
Knockout Mice
Drinking Water
Muscle Cells
Infarction
Echocardiography
Coronary Vessels
Nitric Oxide
Protein Isoforms
Collagen

Keywords

  • Ejection time
  • Oxidative stress
  • Reactive oxygen species

ASJC Scopus subject areas

  • Physiology

Cite this

Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction. / Liu, Yun He; Carretero, Oscar A.; Cingolani, Oscar; Liao, Tang Dong; Sun, Ying; Xu, Jiang; Li, Lisa Y.; Pagano, Patrick J.; Yang, James J.; Yang, Xiao Ping.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 289, No. 6 58-6, 12.2005.

Research output: Contribution to journalArticle

Liu, Yun He ; Carretero, Oscar A. ; Cingolani, Oscar ; Liao, Tang Dong ; Sun, Ying ; Xu, Jiang ; Li, Lisa Y. ; Pagano, Patrick J. ; Yang, James J. ; Yang, Xiao Ping. / Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction. In: American Journal of Physiology - Heart and Circulatory Physiology. 2005 ; Vol. 289, No. 6 58-6.
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abstract = "Using inducible nitric oxide (NO) synthase (iNOS) knockout mice (iNOS -/-), we tested the hypotheses that 1) lack of iNOS attenuates cardiac remodeling and dysfunction and improves cardiac reserve postmyocardial infarction (MI), an effect that is partially mediated by reduction of oxidative stress due to reduced interaction between NO and reactive oxygen species (ROS); and 2) the cardioprotection afforded by iNOS deletion is eliminated by N ω-nitro-L-arginine methyl ester (L-NAME) due to inhibition of endothelial NOS (eNOS) and neuronal NOS (nNOS). MI was induced by ligating the left anterior descending coronary artery. Male iNOS-/- mice and wild-type controls (WT, C57BL/6J) were divided into sham MI, MI+vehicle, and MI+L-NAME (100 mg·kg-1·day-1 in drinking water for 8 wk). Cardiac function was evaluated by echocardiography. Left ventricular (LV) maximum rate of rise of ventricular pressure divided by pressure at the moment such maximum occurs (dP/dt/instant pressure) in response to isoproterenol (100 ng·kg-1·min-1 iv) was measured with a Millar catheter. Collagen deposition, myocyte cross-sectional area, and expression of nitrotyrosine and 4-hydroxy-2-nonenal (4-HNE), markers for ROS, were determined by histopathological and immunohistochemical staining. We found that the MI-induced increase in LV chamber dimension and the decrease in ejection fraction, an index of systolic function, were less severe in iNOS-/- compared with WT mice. L-NAME worsened LV remodeling and dysfunction further, and these detrimental effects were also attenuated in iNOS-/- mice, associated with better preservation of cardiac function. Lack of iNOS also reduced nitrotyrosine and 4-HNE expression after MI, indicating reduced oxidative stress. We conclude that iNOS does not seem to be a pathological mediator of heart failure; however, the lack of iNOS improves cardiac reserve post-MI, particularly when constitutive NOS isoforms are blocked. Decreased oxidative stress and other adaptive mechanisms independent of NOS may be partially responsible for such an effect, which needs to be studied further.",
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AU - Carretero, Oscar A.

AU - Cingolani, Oscar

AU - Liao, Tang Dong

AU - Sun, Ying

AU - Xu, Jiang

AU - Li, Lisa Y.

AU - Pagano, Patrick J.

AU - Yang, James J.

AU - Yang, Xiao Ping

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N2 - Using inducible nitric oxide (NO) synthase (iNOS) knockout mice (iNOS -/-), we tested the hypotheses that 1) lack of iNOS attenuates cardiac remodeling and dysfunction and improves cardiac reserve postmyocardial infarction (MI), an effect that is partially mediated by reduction of oxidative stress due to reduced interaction between NO and reactive oxygen species (ROS); and 2) the cardioprotection afforded by iNOS deletion is eliminated by N ω-nitro-L-arginine methyl ester (L-NAME) due to inhibition of endothelial NOS (eNOS) and neuronal NOS (nNOS). MI was induced by ligating the left anterior descending coronary artery. Male iNOS-/- mice and wild-type controls (WT, C57BL/6J) were divided into sham MI, MI+vehicle, and MI+L-NAME (100 mg·kg-1·day-1 in drinking water for 8 wk). Cardiac function was evaluated by echocardiography. Left ventricular (LV) maximum rate of rise of ventricular pressure divided by pressure at the moment such maximum occurs (dP/dt/instant pressure) in response to isoproterenol (100 ng·kg-1·min-1 iv) was measured with a Millar catheter. Collagen deposition, myocyte cross-sectional area, and expression of nitrotyrosine and 4-hydroxy-2-nonenal (4-HNE), markers for ROS, were determined by histopathological and immunohistochemical staining. We found that the MI-induced increase in LV chamber dimension and the decrease in ejection fraction, an index of systolic function, were less severe in iNOS-/- compared with WT mice. L-NAME worsened LV remodeling and dysfunction further, and these detrimental effects were also attenuated in iNOS-/- mice, associated with better preservation of cardiac function. Lack of iNOS also reduced nitrotyrosine and 4-HNE expression after MI, indicating reduced oxidative stress. We conclude that iNOS does not seem to be a pathological mediator of heart failure; however, the lack of iNOS improves cardiac reserve post-MI, particularly when constitutive NOS isoforms are blocked. Decreased oxidative stress and other adaptive mechanisms independent of NOS may be partially responsible for such an effect, which needs to be studied further.

AB - Using inducible nitric oxide (NO) synthase (iNOS) knockout mice (iNOS -/-), we tested the hypotheses that 1) lack of iNOS attenuates cardiac remodeling and dysfunction and improves cardiac reserve postmyocardial infarction (MI), an effect that is partially mediated by reduction of oxidative stress due to reduced interaction between NO and reactive oxygen species (ROS); and 2) the cardioprotection afforded by iNOS deletion is eliminated by N ω-nitro-L-arginine methyl ester (L-NAME) due to inhibition of endothelial NOS (eNOS) and neuronal NOS (nNOS). MI was induced by ligating the left anterior descending coronary artery. Male iNOS-/- mice and wild-type controls (WT, C57BL/6J) were divided into sham MI, MI+vehicle, and MI+L-NAME (100 mg·kg-1·day-1 in drinking water for 8 wk). Cardiac function was evaluated by echocardiography. Left ventricular (LV) maximum rate of rise of ventricular pressure divided by pressure at the moment such maximum occurs (dP/dt/instant pressure) in response to isoproterenol (100 ng·kg-1·min-1 iv) was measured with a Millar catheter. Collagen deposition, myocyte cross-sectional area, and expression of nitrotyrosine and 4-hydroxy-2-nonenal (4-HNE), markers for ROS, were determined by histopathological and immunohistochemical staining. We found that the MI-induced increase in LV chamber dimension and the decrease in ejection fraction, an index of systolic function, were less severe in iNOS-/- compared with WT mice. L-NAME worsened LV remodeling and dysfunction further, and these detrimental effects were also attenuated in iNOS-/- mice, associated with better preservation of cardiac function. Lack of iNOS also reduced nitrotyrosine and 4-HNE expression after MI, indicating reduced oxidative stress. We conclude that iNOS does not seem to be a pathological mediator of heart failure; however, the lack of iNOS improves cardiac reserve post-MI, particularly when constitutive NOS isoforms are blocked. Decreased oxidative stress and other adaptive mechanisms independent of NOS may be partially responsible for such an effect, which needs to be studied further.

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