Nitric oxide synthase 3 deficiency limits adverse ventricular remodeling after pressure overload in insulin resistance

Baptiste Kurtz, Helene B. Thibault, Michael J. Raher, John R. Popovich, Sharon Cawley, Dmitriy N. Atochin, Sarah Hayton, Hannah R. Shakartzi, Paul L. Huang, Kenneth D. Bloch, Emmanuel Buys, Marielle Scherrer-Crosbie

Research output: Contribution to journalArticle

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Abstract

Insulin resistance (IR) and systemic hypertension are independently associated with heart failure. We reported previously that nitric oxide synthase 3 (NOS3) has a beneficial effect on left ventricular (LV) remodeling and function after pressure-overload in mice. The aim of our study was to investigate the interaction of IR and NOS3 in pressure-overload-induced LV remodeling and dysfunction. Wild-type (WT) and NOS3-deficient (NOS3~ /~) mice were fed either a standard diet (SD) or a high-fat diet (HFD) to induce IR. After 9 days of diet, mice underwent transverse aortic constriction (TAC). LV structure and function were assessed serially using echocardiography. Cardiomyocytes were isolated, and levels of oxidative stress were evaluated using 2',7'-dichlorodihydrofluorescein diacetate. Cardiac mitochondria were isolated, and mitochondrial respiration and ATP production were measured. TAC induced LV remodeling and dysfunction in all mice. The TAC-induced decrease in LV function was greater in SD-fed NOS3~ /~ mice than in SD-fed WT mice. In contrast, HFD-fed NOS3~ /~ developed less LV remodeling and dysfunction and had better survival than did HFD-fed WT mice. Seven days after TAC, oxidative stress levels were lower in cardiomyocytes from HFD-fed NOS3~ /~ than in those from HFD-fed WT. N^-nitro-L-arginine methyl ester and mitochondrial inhibitors (rotenone and 2-thenoyltri-fluoroacetone) decreased oxidative stress levels in cardiomyocytes from HFD-fed WT mice. Mitochondrial respiration was altered in NOS3~ /~ mice but did not worsen after HFD and TAC. In contrast with its protective role in SD, NOS3 increases LV adverse remodeling after pressure overload in HFD-fed, insulin resistant mice. Interactions between NOS3 and mitochondria may be responsible for increased oxidative stress levels in HFD-fed WT mice hearts.

Original languageEnglish
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume301
Issue number5
DOIs
Publication statusPublished - Nov 2011
Externally publishedYes

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Ventricular Remodeling
Nitric Oxide Synthase
High Fat Diet
Insulin Resistance
Pressure
Constriction
Diet
Left Ventricular Dysfunction
Oxidative Stress
Left Ventricular Function
Cardiac Myocytes
Mitochondria
Respiration
Rotenone
Nitric Oxide Synthase Type III
Echocardiography
Heart Failure
Adenosine Triphosphate
Insulin
Hypertension

Keywords

  • Cardiac dysfunction
  • Oxidative stress

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Nitric oxide synthase 3 deficiency limits adverse ventricular remodeling after pressure overload in insulin resistance. / Kurtz, Baptiste; Thibault, Helene B.; Raher, Michael J.; Popovich, John R.; Cawley, Sharon; Atochin, Dmitriy N.; Hayton, Sarah; Shakartzi, Hannah R.; Huang, Paul L.; Bloch, Kenneth D.; Buys, Emmanuel; Scherrer-Crosbie, Marielle.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 301, No. 5, 11.2011.

Research output: Contribution to journalArticle

Kurtz, B, Thibault, HB, Raher, MJ, Popovich, JR, Cawley, S, Atochin, DN, Hayton, S, Shakartzi, HR, Huang, PL, Bloch, KD, Buys, E & Scherrer-Crosbie, M 2011, 'Nitric oxide synthase 3 deficiency limits adverse ventricular remodeling after pressure overload in insulin resistance', American Journal of Physiology - Heart and Circulatory Physiology, vol. 301, no. 5. https://doi.org/10.1152/ajpheart.00744.2010
Kurtz, Baptiste ; Thibault, Helene B. ; Raher, Michael J. ; Popovich, John R. ; Cawley, Sharon ; Atochin, Dmitriy N. ; Hayton, Sarah ; Shakartzi, Hannah R. ; Huang, Paul L. ; Bloch, Kenneth D. ; Buys, Emmanuel ; Scherrer-Crosbie, Marielle. / Nitric oxide synthase 3 deficiency limits adverse ventricular remodeling after pressure overload in insulin resistance. In: American Journal of Physiology - Heart and Circulatory Physiology. 2011 ; Vol. 301, No. 5.
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