title: Bone Morphogenic Protein 4 Mediates NOX1-Dependent eNOS Uncoupling, Endothelial Dysfunction, and COX2 Induction in Type 2 Diabetes Mellitus.
abstract: We have recently shown that angiotensin II-mediated uncoupling of endothelial nitric oxide synthase (eNOS) contributes to endothelial dysfunction in streptozotocin-induced type 1 diabetes mellitus. However, it has remained unclear whether and how eNOS uncoupling occurs in type 2 diabetes mellitus (T2DM) and the consequences of such in regulating vascular function. Here we investigated a role of bone morphogenic protein (BMP)-4 in mediating eNOS uncoupling, endothelial dysfunction, and inflammation in db/db mice. Circulating levels of BMP4 were markedly elevated in db/db mice but not in mice with type 1 diabetes mellitus, in which angiotensin II levels were significantly increased. Infusion of BMP4 antagonist noggin into db/db mice (15 μg/kg/day, 4 weeks) abolished eNOS uncoupling activity while restoring tetrahydrobiopterin (H(4)B) bioavailability. The impaired endothelium-dependent vasorelaxation in db/db aortas was significantly improved by noggin infusion. Exposure of aortic endothelial cells to BMP4 (50 ng/mL, 24 hours) resulted in eNOS uncoupling, which was attenuated by H(4)B precursor sepiapterin or small interfering RNA silencing nicotinamide adenine dinucleotide phosphate oxidase isoform 1 (NOX1). Interestingly, BMP4-dependent NOX1 up-regulation was abrogated by sepiapterin, implicating a NOX1-uncoupled eNOS-NOX1 feed-forward loop. BMP4 induction of cyclooxygenase 2 (COX2) expression and vascular cell adhesion protein 1 was found in db/db mice. Consistently, COX2 was up-regulated by BMP4 in endothelial cells, which was attenuated by sepiapterin, implicating an upstream role of eNOS uncoupling in COX2-mediated inflammatory activation. Taken together, our data for the first time reveal a novel role of BMP4 in inducing NOX1-dependent eNOS uncoupling in T2DM, which may promote development of novel therapeutics restoring endothelial function in T2DM.
authors.affiliation: Divisions of Molecular Medicine and Cardiology, Departments of Anesthesiology and Medicine, Cardivascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095.
authors.forename: Ji-Youn
authors.initials: JY
authors.lastname: Youn
authors.affiliation: Divisions of Molecular Medicine and Cardiology, Departments of Anesthesiology and Medicine, Cardivascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Divisions of Molecular Medicine and Cardiology, Departments of Anesthesiology and Medicine, Cardivascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095.
authors.forename: Hua
authors.initials: H
authors.lastname: Cai
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000473:pathology; D001708:Biopterins / Q000031:analogs & derivatives / Q000737:chemistry; D001786:Blood Glucose / Q000737:chemistry; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D000099176:Noggin Protein
chemical_list: D000804:Angiotensin II; D001708:Biopterins; D001786:Blood Glucose; D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D002784:Cholesterol; D051546:Cyclooxygenase 2; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D052250:Nitric Oxide Synthase Type III; D034741:RNA, Small Interfering; D013481:Superoxides; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse; C496315:Nos3 protein, mouse; C077623:Ptgs2 protein, mouse; C000614711:NOX1 protein, mouse; C003402:sapropterin