Endothelial nitric oxide synthase enhancer reduces oxidative stress and restores endothelial function in db/db mice

Wai San Cheang, Wing Tak Wong, Xiao Yu Tian, Qin Yang, Hung Kay Lee, Guo Wei He, Xiaoqiang Yao, Yu Huang

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


AimsEndothelial dysfunction is caused by reduced nitric oxide (NO) bioavailability and/or over-produced reactive oxygen species (ROS). The present study investigated a vascular benefit of AVE3085, an endothelial nitric oxide synthase (eNOS) enhancer, in preserving endothelial function in diabetic mice and the mechanisms involved.Methods and resultsMale db/db and db/m + mice were orally administered AVE3085 for 7 days (10 mg kg -1 day -1). Vascular reactivity of arteries was studied via myography under both isometric and isobaric conditions. ROS levels in aortas were determined using dihydroethidium fluorescence dye and electron paramagnetic resonance spin trapping. Chronic treatment with AVE3085 reduced blood pressure, enhanced endothelium-dependent relaxations (EDR) to acetylcholine in aortas, mesenteric, and renal arteries, lowered oxidative stress, and augmented the attenuated flow-dependent dilatation in mesenteric resistance arteries from db/db mice. Incubation of aortas from C57BL/6J mice in high glucose (30 mmol L -1) culture medium for 48 h impaired EDR and elevated ROS generation, and these effects were reversed by co-treatment with AVE3085 (1 mol L -1). Benefits of AVE3085 were abolished by the transcription inhibitor actinomycin D, the NOS inhibitor N G-nitro-l-arginine methyl ester, and in eNOS -/- mice. NO production in primary endothelial cells from mouse aortas was detected with a NO-sensitive fluorescence dye. Protein expression was assayed by western blotting. Treatment with AVE3085 enhanced NO production in endothelial cells and eNOS expression in aortas.ConclusionAVE3085 ameliorates endothelial dysfunction in db/db mice through increased NO bioavailability, which reduces oxidative stress in the vascular wall. Targeting eNOS and NO production may be a promising approach to combat diabetic vasculopathy.

Original languageEnglish (US)
Pages (from-to)267-275
Number of pages9
JournalCardiovascular Research
Issue number2
StatePublished - Nov 1 2011


  • Diabetes
  • Endothelial NOS enhancer
  • Endothelium
  • Oxidative stress

ASJC Scopus subject areas

  • Medicine(all)


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