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Nox1 Deletion Rescues Microvascular Dysfunction in Obese Mice
Author(s) -
Thompson Jennifer Anne,
Mintz James,
Fulton David J,
Stepp David W
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.952.9
Subject(s) - endocrinology , medicine , chemistry , triglyceride , nox1 , obesity , nitric oxide , endothelial dysfunction , nadph oxidase , cholesterol , oxidative stress
Objective To investigate the role of Nox1 in the development of microvascular dysfunction in obesity. Methods Four genotypes were generated by breeding Nox1 knock‐out (KO) mice with obese db/db mice: (H db W nox1 ); lean Nox1 KO (H db K nox1 ); obese (K db W nox1 ); double KO (K db K nox1 ). At 12 weeks of age, body composition was determined by NMR spectroscopy and fasting levels of lipids, glucose and HbA1c were measured. Glucose tolerance tests in conscious mice were generated after IP injection of a glucose load (2g/kg body weight). Mesenteric arteries were isolated and endothelium‐dependent responses to acetylcholine (Ach) (10 −12 –10 −3 M) were assessed in the presence or absence of L‐NAME (inhibitor of nitric oxide synthase) or Tempol (superoxide dismutase mimetic). Results Body weight and % body fat were increased in obese (KW, KK) vs. lean (HW, HK) mice (p < 0.01), while there were no differences in KW vs. KK (% body fat, HW: 16.3 ± 2.5 %; KW: 61.2 ± 5.2 %; HK: 14.2 ± 1.2 %; KK: 50.3 ± 5.0 %). Likewise, fasting plasma glucose, HbA1c, insulin and triglyceride levels were elevated in obese mice (p < 0.01), with no differences between KW and KK. The area under the curve for glucose tolerance tests was increased by 67% in HW vs. KW and 60% in HK vs. KK (p < 0.05). KK and KW mice also exhibited similar reductions in oxygen consumption and carbon dioxide production (p < 0.01). Endothelium‐dependent responses to Ach were blunted by 48% in obese (KW) vs. lean (HW) (p < 0.01), yet similar between obese mice with Nox1 deletion (KK) and lean controls (HK). L‐NAME incubation reduced Ach responses in HW, HK and KK animals (p < 0.01), but had no influence in KW. Tempol had no impact on HW, HK and KK, but improved Ach responses in KW mice. Conclusions Impaired endothelial function in the microvasculature of obese db/db mice appears to be related to vascular superoxide production. Deletion of Nox1 improved microvascular endothelial function in obese db/db mice without influencing the degree of adiposity, hyperglycemia or dyslipidemia. Therefore, Nox1 may be an effective target for the prevention of vascular disease in the metabolic syndrome. Support or Funding Information DWS is supported by AHA‐GIA and NHLR01 98744; JAT supported by AHA 15POST25730006