title: Inhibition of bone morphogenic protein 4 restores endothelial function in db/db diabetic mice.
abstract: 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.
  
  
  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.
authors.affiliation: From the Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences (Y.Z., L.W., J.L., W.S.C., C.W.L., X.Y., Y.H.), School of Biomedical Sciences (J.L., Y.C., X.Y., Y.H.), School of Life Sciences (K.M.K.), Chinese University of Hong Kong, Hong Kong SAR, China; Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX (X.Y.T., W.T.W.); and Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing, China (N.W.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Xiao Yu
authors.initials: XY
authors.lastname: Tian
authors.forename: Wing Tak
authors.initials: WT
authors.lastname: Wong
authors.forename: Yangchao
authors.initials: Y
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Jiangyun
authors.initials: J
authors.lastname: Luo
authors.forename: Wai San
authors.initials: WS
authors.lastname: Cheang
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Lau
authors.forename: Kin Ming
authors.initials: KM
authors.lastname: Kwan
authors.forename: Nanping
authors.initials: N
authors.lastname: Wang
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Yao
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology*; D002478:Cells, Cultured; D003925:Diabetic Angiopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology; D000099176:Noggin Protein
chemical_list: D000109:Acetylcholine; D001786:Blood Glucose; D055415:Bone Morphogenetic Protein 4; D052005:Bone Morphogenetic Protein Receptors, Type I; D002352:Carrier Proteins; D009569:Nitric Oxide; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse; C498212:Bmpr1a protein, mouse
keywords: bone morphogenetic protein 4, mouse; diabetes mellitus; endothelial dysfunction; reactive oxygen species