title: Bone morphogenic protein-4 impairs endothelial function through oxidative stress-dependent cyclooxygenase-2 upregulation: implications on hypertension.
abstract: BACKGROUND
  Bone morphogenic protein (BMP)4 can stimulate superoxide production and exert proinflammatory effects on the endothelium. The underlying mechanisms of how BMP4 mediates endothelial dysfunction and hypertension remain elusive.
  
  
  OBJECTIVE
  To elucidate the cellular pathways by which BMP4-induced endothelial dysfunction is mediated through oxidative stress-dependent upregulation of cyclooxygenase (COX)-2.
  
  
  RESULTS
  Impaired endothelium-dependent relaxations, exaggerated endothelium-dependent contractions, and reactive oxygen species (ROS) production were observed in BMP4-treated mouse aortae, which were prevented by the BMP4 antagonist noggin. Pharmacological inhibition with thromboxane prostanoid receptor antagonist or COX-2 but not COX-1 inhibitor prevented BMP4-induced endothelial dysfunction, which was further confirmed with the use of COX-1(-/-) or COX-2(-/-) mice. Noggin and knockdown of BMP receptor 1A abolished endothelium-dependent contractions and COX-2 upregulation in BMP4-treated aortae. Apocynin and tempol treatment were effective in restoring endothelium-dependent relaxations, preventing endothelium-dependent contractions and eliminating ROS overproduction and COX-2 overexpression in BMP4-treated aortae. BMP4 increased p38 mitogen-activated protein kinase (MAPK) activity through a ROS-sensitive mechanism and p38 MAPK inhibitor prevented BMP4-induced endothelial dysfunction. COX-2 inhibition blocked the effect of BMP4 without affecting BMP4-induced ROS overproduction and COX-2 upregulation. Importantly, renal arteries from hypertensive rats and humans showed higher levels of COX-2 and BMP4 accompanied by endothelial dysfunction.
  
  
  CONCLUSIONS
  We show for the first time that ROS serve as a pathological link between BMP4 stimulation and the downstream COX-2 upregulation in endothelial cells, leading to endothelial dysfunction through ROS-dependent p38 MAPK activation. This BMP4/ROS/COX-2 cascade is important in the maintenance of endothelial dysfunction in hypertension.
authors: School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, NT, Hong Kong, China. jack_wong@cuhk.edu.hk
authors: Wing Tak
authors: WT
authors: Wong
authors: Xiao Yu
authors: XY
authors: Tian
authors: Yangchao
authors: Y
authors: Chen
authors: Fung Ping
authors: FP
authors: Leung
authors: Limei
authors: L
authors: Liu
authors: Hung Kay
authors: HK
authors: Lee
authors: Chi Fai
authors: CF
authors: Ng
authors: Aimin
authors: A
authors: Xu
authors: Xiaoqiang
authors: X
authors: Yao
authors: Paul M
authors: PM
authors: Vanhoutte
authors: George L
authors: GL
authors: Tipoe
authors: Yu
authors: Y
authors: Huang
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D006977:Hypertension, Renal / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism; D012077:Renal Artery / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099176:Noggin Protein
chemical_list: D055415:Bone Morphogenetic Protein 4; D052005:Bone Morphogenetic Protein Receptors, Type I; D002352:Carrier Proteins; D051546:Cyclooxygenase 2; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; D000099176:Noggin Protein; C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; C525811:Bmp4 protein, rat; C077623:Ptgs2 protein, mouse; C489691:Ptgs2 protein, rat