title: Anti-inflammatory and antiatherogenic role of BMP receptor II in endothelial cells.
abstract: OBJECTIVE
  Atherosclerosis is an inflammatory disease with multiple underlying metabolic and physical risk factors. Bone morphogenic protein 4 (BMP4) expression is increased in endothelium in atherosclerosis-prone regions and is known to induce endothelial inflammation, endothelial dysfunction, and hypertension. BMP actions are mediated by 2 different types of BMP receptors (BMPRI and BMPRII). Here, we show a surprising finding that loss of BMPRII expression causes endothelial inflammation and atherosclerosis.
  
  
  RESULTS
  Using BMPRII siRNA and BMPRII(+/-) mice, we found that specific knockdown of BMPRII, but not other BMP receptors (Alk1, Alk2, Alk3, Alk6, ActRIIa, and ActRIIb), induced endothelial inflammation in a ligand-independent manner by mechanisms mediated by reactive oxygen species, nuclear factor-KappaB, and reduced nicotinamide adenine dinucleotide phosphate oxidases. Further, BMPRII(+/-)ApoE(-/-) mice developed accelerated atherosclerosis compared with BMPRII(+/+)ApoE(-/-) mice. Interestingly, we found that multiple proatherogenic stimuli, such as hypercholesterolemia, disturbed flow, prohypertensive angiotensin II, and the proinflammatory cytokine (tumor necrosis factor-α), downregulated BMPRII expression in endothelium, whereas antiatherogenic stimuli, such as stable flow and statin treatment, upregulated its expression in vivo and in vitro. Moreover, BMPRII expression was significantly diminished in human coronary advanced atherosclerotic lesions. Also, we were able to rescue the endothelial inflammation induced by BMPRII knockdown by overexpressing the BMPRII wild type, but not by the BMPRII short form lacking the carboxyl-terminal tail region.
  
  
  CONCLUSIONS
  These results suggest that BMPRII is a critical, anti-inflammatory, and antiatherogenic protein that is commonly targeted by multiple pro- and antiatherogenic factors. BMPRII may be used as a novel diagnostic and therapeutic target in atherosclerosis.
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA.
authors.forename: Chan Woo
authors.initials: CW
authors.lastname: Kim
authors.forename: Hannah
authors.initials: H
authors.lastname: Song
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kumar
authors.forename: Douglas
authors.initials: D
authors.lastname: Nam
authors.forename: Hyuk Sang
authors.initials: HS
authors.lastname: Kwon
authors.forename: Kyung Hwa
authors.initials: KH
authors.lastname: Chang
authors.forename: Dong Ju
authors.initials: DJ
authors.lastname: Son
authors.forename: Dong-Won
authors.initials: DW
authors.lastname: Kang
authors.forename: Seth A
authors.initials: SA
authors.lastname: Brodie
authors.forename: Daiana
authors.initials: D
authors.lastname: Weiss
authors.forename: J David
authors.initials: JD
authors.lastname: Vega
authors.forename: Noah
authors.initials: N
authors.lastname: Alberts-Grill
authors.forename: Kathy
authors.initials: K
authors.lastname: Griendling
authors.forename: W Robert
authors.initials: WR
authors.lastname: Taylor
authors.forename: Hanjoong
authors.initials: H
authors.lastname: Jo
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012016:Reference Values; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D052004:Bone Morphogenetic Protein Receptors
keywords: BMPRII; atherosclerosis; blood flow; endothelial cell; inflammation; signal transduction
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