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

作者：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 Cro**ie Marielle^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2011, 301(5): H2093-H2101.

DOI：10.1152/ajpheart.00744.2010

• oxidative stress
• cardiac dysfunction

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. Nitric oxide synthase 3 deficiency limits adverse ventricular remodeling after pressure overload in insulin resistance. Am J Physiol Heart Circ Physiol 301: H2093-H2101, 2011. First published August 19, 2011; doi:10.1152/ajpheart.00744.2010.-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(omega)-nitro-L-arginine methyl ester and mitochondrial inhibitors (rotenone and 2-thenoyltrifluoroacetone) 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.

• 出版日期2011-11