Inhibition of bone morphogenic protein 4 restores endothelial function in db/db diabetic mice.

نویسندگان

  • Yang Zhang
  • Jian Liu
  • Xiao Yu Tian
  • Wing Tak Wong
  • Yangchao Chen
  • Li Wang
  • Jiangyun Luo
  • Wai San Cheang
  • Chi Wai Lau
  • Kin Ming Kwan
  • Nanping Wang
  • Xiaoqiang Yao
  • Yu Huang
چکیده

OBJECTIVE Bone morphogenic protein 4 (BMP4) is involved in the development of endothelial dysfunction in hypertension. This study investigated whether the inhibition of BMP4 signaling improves endothelial function in db/db diabetic mice. APPROACH AND RESULTS Male db/db mice were treated with noggin via osmotic pump infusion (1 µg/[h·kg(-1)]) for 2 weeks. Adenovirus BMP4-short hairpin RNA was introduced via tail vein injection at a dosage of 10(9) pfu/mouse and its effects were examined 7 days after. Vasoreactivity was studied on wire and pressure myograph. Both noggin treatment and adenovirus BMP4-short hairpin RNA transduction improved endothelium-dependent relaxations in aortae and flow-mediated dilatation in mesenteric arteries of db/db mice. Ex vivo treatment with BMP4 inhibitors and adenovirus BMP4-short hairpin RNA rescued the impaired endothelium-dependent relaxations in db/db mouse aortae and reduced reactive oxygen species overproduction determined by dihydroethidium staining, CM-H2DCFDA fluorescence imaging, and chemiluminescence assay in db/db mouse aortae, and also in ex vivo cultured C57BL/6 mouse aortae or primary mouse aortic endothelial cells treated with high glucose. Likewise, activin receptor-like kinase 3 silencing by short hairpin RNA lentivirus improved endothelium-dependent relaxations in db/db mouse aortae accompanied by reactive oxygen species inhibition in endothelial cells. In addition, noggin reduced BMP4 upregulation in high-glucose-treated endothelial cells and in C57BL/6 mouse aortae and in aortae from db/db mice. CONCLUSIONS Inhibition of BMP4/activin receptor-like kinase 3/reactive oxygen species signaling improved endothelial function in diabetic mice through limiting oxidative stress in endothelium. Inhibiting BMP4 cascade can become another potential therapeutic strategy against diabetic vascular dysfunction.

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عنوان ژورنال:
  • Arteriosclerosis, thrombosis, and vascular biology

دوره 34 1  شماره 

صفحات  -

تاریخ انتشار 2014