title: Nitric oxide synthase 3 deficiency limits adverse ventricular remodeling after pressure overload in insulin resistance.
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(ω)-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.
authors.affiliation: Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Kurtz
authors.forename: Helene B
authors.initials: HB
authors.lastname: Thibault
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Raher
authors.forename: John R
authors.initials: JR
authors.lastname: Popovich
authors.forename: Sharon
authors.initials: S
authors.lastname: Cawley
authors.forename: Dmitriy N
authors.initials: DN
authors.lastname: Atochin
authors.forename: Sarah
authors.initials: S
authors.lastname: Hayton
authors.forename: Hannah R
authors.initials: HR
authors.lastname: Shakartzi
authors.forename: Paul L
authors.initials: PL
authors.lastname: Huang
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Buys
authors.forename: Marielle
authors.initials: M
authors.lastname: Scherrer-Crosbie
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D006861:Hydrogen Peroxide / Q000378:metabolism; D006973:Hypertension / Q000150:complications* / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D018384:Oxidative Stress; D010766:Phosphorylation; D012694:Serine; D013997:Time Factors; D014463:Ultrasonography; D014475:Uncoupling Agents / Q000494:pharmacology; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D004041:Dietary Fats; D004791:Enzyme Inhibitors; D014475:Uncoupling Agents; D012694:Serine; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse