Nox1 Deletion Rescues Microvascular Dysfunction in Obese db/db Mice

Abstract

Objective To explore Nox1 as a mechanism of microvascular dysfunction in metabolic disease. Methods: Four genotypes were generated by breeding Nox1 knock-out (KO) mice with db/db mice: lean (HdbWnox1); lean Nox1 KO (HdbKnox1); obese (KdbWnox1); double KO (KdbKnox1). At 12 weeks, body composition (NMR spectroscopy), fasting blood glucose (FBG) and HbA1c levels were assessed. Mesenteric arteries were isolated and endothelium-dependent function assessed via pressure myography using the dilatory response to cumulative doses of acetylcholine (Ach: 10-12-10-3 M). Results: Nox1 deletion did not affect the development of visceral obesity in db/db mice or body composition in lean controls. Body weight, visceral fat weight and % body fat increased in KW vs. HW (p < 0.01) and in KK vs. HK (p < 0.01). Severe hyperglycaemia was apparent in obese mice with and without Nox1, and Nox1 deletion had no impact on glucose homeostasis in lean controls (FBG: HW = 209.00 ± 17.21 mg/dL vs. KW = 434.80 ± 65.34 mg/dL, p < 0.001; HK = 180.20 ± 19.38 mg/dL vs. KK = 496.80 ± 37.73 mg/dL, p < 0.001; HbA1c: HW = 4.71 ± 0.09 % vs. KW = 8.46 ± 1.07 %, p < 0.001; HK = 4.46 ± 0.09 % vs. KK = 12.43 ± 0.35 %, p <0.001). Triglycerides were increased in obese mice; NOX1 deletion had no effect (HW = 34.64 ± 3.84 mg/dL vs. KW = 136.50 ± 13.40 mg/dL, p < 0.001; HK = 29.85 ± 3.82 mg/dL vs. KK = 162.00 ± 30.07 mg/dL, p < 0.001). Ach responses in obese mice with Nox1 deletion were comparable to the lean groups, yet blunted in KW (Emax: HW = 58.40 ± 3.58% vs. KW = 34.69 ± 5.18 %, p < 0.05; HK = 58.69 ± 5.40 %; KK = 57.71 ± 8.07 %). Conclusions Nox1 deletion rescued endothelial function in obese mice despite persistent metabolic disease. Thus, the metabolic milieu of obesity may be transduced to the endothelium via Nox1. DWS funded by AHA-GIA and NHLR01