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Article: Bone morphogenic protein-4 impairs endothelial function through oxidative stress-dependent cyclooxygenase-2 upregulation: Implications on hypertension

TitleBone morphogenic protein-4 impairs endothelial function through oxidative stress-dependent cyclooxygenase-2 upregulation: Implications on hypertension
Authors
Keywordsbone morphogenic protein 4
cyclooxygenase-2
endothelial dysfunction
endothelium-dependent contractions
reactive oxygen species
Issue Date2010
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://circres.ahajournals.org
Citation
Circulation Research, 2010, v. 107 n. 8, p. 984-991 How to Cite?
AbstractRationale: 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. Methods and 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. © 2010 American Heart Association. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/149751
ISSN
2015 Impact Factor: 11.551
2015 SCImago Journal Rankings: 5.755
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grant CouncilCUHK465308
CUHK466110
HKU 2/07C
CUHK Focused Investment Scheme
Funding Information:

This work was supported by the Hong Kong Research Grant Council (CUHK465308, CUHK466110, and HKU 2/07C) and CUHK Focused Investment Scheme.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorWong, WTen_HK
dc.contributor.authorTian, XYen_HK
dc.contributor.authorChen, Yen_HK
dc.contributor.authorLeung, FPen_HK
dc.contributor.authorLiu, Len_HK
dc.contributor.authorLee, HKen_HK
dc.contributor.authorNg, CFen_HK
dc.contributor.authorXu, Aen_HK
dc.contributor.authorYao, Xen_HK
dc.contributor.authorVanhoutte, PMen_HK
dc.contributor.authorTipoe, GLen_HK
dc.contributor.authorHuang, Yen_HK
dc.date.accessioned2012-06-26T05:58:03Z-
dc.date.available2012-06-26T05:58:03Z-
dc.date.issued2010en_HK
dc.identifier.citationCirculation Research, 2010, v. 107 n. 8, p. 984-991en_HK
dc.identifier.issn0009-7330en_HK
dc.identifier.urihttp://hdl.handle.net/10722/149751-
dc.description.abstractRationale: 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. Methods and 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. © 2010 American Heart Association. All rights reserved.en_HK
dc.languageengen_US
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://circres.ahajournals.orgen_HK
dc.relation.ispartofCirculation Researchen_HK
dc.subjectbone morphogenic protein 4en_HK
dc.subjectcyclooxygenase-2en_HK
dc.subjectendothelial dysfunctionen_HK
dc.subjectendothelium-dependent contractionsen_HK
dc.subjectreactive oxygen speciesen_HK
dc.subject.meshAnimalsen_US
dc.subject.meshAorta - Metabolismen_US
dc.subject.meshBone Morphogenetic Protein 4 - Antagonists & Inhibitors - Metabolismen_US
dc.subject.meshBone Morphogenetic Protein Receptors, Type I - Metabolismen_US
dc.subject.meshCarrier Proteins - Metabolism - Pharmacologyen_US
dc.subject.meshCyclooxygenase 2 - Genetics - Metabolismen_US
dc.subject.meshEndothelium, Vascular - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshHypertension, Renal - Metabolismen_US
dc.subject.meshMap Kinase Signaling System - Physiologyen_US
dc.subject.meshMaleen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Inbred C57blen_US
dc.subject.meshOxidative Stress - Physiologyen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Inbred Shren_US
dc.subject.meshRats, Inbred Wkyen_US
dc.subject.meshReactive Oxygen Species - Metabolismen_US
dc.subject.meshRenal Artery - Physiologyen_US
dc.subject.meshUp-Regulation - Drug Effects - Physiologyen_US
dc.subject.meshP38 Mitogen-Activated Protein Kinases - Metabolismen_US
dc.titleBone morphogenic protein-4 impairs endothelial function through oxidative stress-dependent cyclooxygenase-2 upregulation: Implications on hypertensionen_HK
dc.typeArticleen_HK
dc.identifier.emailXu, A: amxu@hkucc.hku.hken_HK
dc.identifier.emailVanhoutte, PM: vanhoutt@hku.hken_HK
dc.identifier.emailTipoe, GL: tgeorge@hkucc.hku.hken_HK
dc.identifier.authorityXu, A=rp00485en_HK
dc.identifier.authorityVanhoutte, PM=rp00238en_HK
dc.identifier.authorityTipoe, GL=rp00371en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1161/CIRCRESAHA.110.222794en_HK
dc.identifier.pmid20724703-
dc.identifier.scopuseid_2-s2.0-77958496539en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77958496539&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume107en_HK
dc.identifier.issue8en_HK
dc.identifier.spage984en_HK
dc.identifier.epage991en_HK
dc.identifier.isiWOS:000282965300007-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectVascular dysfunction in obesity and diabetes: from risk prediction to therapeutic intervention-
dc.identifier.scopusauthoridWong, WT=35932584500en_HK
dc.identifier.scopusauthoridTian, XY=35768379500en_HK
dc.identifier.scopusauthoridChen, Y=24075600300en_HK
dc.identifier.scopusauthoridLeung, FP=8615375300en_HK
dc.identifier.scopusauthoridLiu, L=36652673500en_HK
dc.identifier.scopusauthoridLee, HK=7501482998en_HK
dc.identifier.scopusauthoridNg, CF=8519137200en_HK
dc.identifier.scopusauthoridXu, A=7202655409en_HK
dc.identifier.scopusauthoridYao, X=7402529434en_HK
dc.identifier.scopusauthoridVanhoutte, PM=7202304247en_HK
dc.identifier.scopusauthoridTipoe, GL=7003550610en_HK
dc.identifier.scopusauthoridHuang, Y=7501573013en_HK

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