PMID- 26121233
OWN - NLM
STAT- MEDLINE
DCOM- 20160510
LR  - 20231213
IS  - 1944-9917 (Electronic)
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 29
IP  - 8
DP  - 2015 Aug
TI  - Bone Morphogenic Protein 4 Mediates NOX1-Dependent eNOS Uncoupling, Endothelial 
      Dysfunction, and COX2 Induction in Type 2 Diabetes Mellitus.
PG  - 1123-33
LID - 10.1210/ME.2014-1313 [doi]
AB  - 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 mug/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.
FAU - Youn, Ji-Youn
AU  - Youn JY
AD  - 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.
FAU - Zhou, Jun
AU  - Zhou J
AD  - 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.
FAU - Cai, Hua
AU  - Cai H
AD  - 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.
LA  - eng
GR  - HL088975/HL/NHLBI NIH HHS/United States
GR  - R01 HL108701/HL/NHLBI NIH HHS/United States
GR  - HL108701/HL/NHLBI NIH HHS/United States
GR  - R01 HL119968/HL/NHLBI NIH HHS/United States
GR  - HL077440/HL/NHLBI NIH HHS/United States
GR  - R01 HL088975/HL/NHLBI NIH HHS/United States
GR  - R01 HL077440/HL/NHLBI NIH HHS/United States
GR  - HL119968/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150629
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (Blood Glucose)
RN  - 0 (Bmp4 protein, mouse)
RN  - 0 (Bone Morphogenetic Protein 4)
RN  - 0 (Carrier Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 11062-77-4 (Superoxides)
RN  - 11128-99-7 (Angiotensin II)
RN  - 148294-77-3 (noggin protein)
RN  - 0 (Biopterins)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 1.14.13.39 (Nos3 protein, mouse)
RN  - EC 1.14.99.- (Ptgs2 protein, mouse)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 1.6.- (NADH, NADPH Oxidoreductases)
RN  - EC 1.6.3.- (NADPH Oxidase 1)
RN  - EC 1.6.3.- (NOX1 protein, mouse)
RN  - EGX657432I (sapropterin)
SB  - IM
MH  - Angiotensin II/metabolism
MH  - Animals
MH  - Aorta/cytology/pathology
MH  - Biopterins/analogs & derivatives/chemistry
MH  - Blood Glucose/chemistry
MH  - Bone Morphogenetic Protein 4/*metabolism
MH  - Carrier Proteins/metabolism
MH  - Cattle
MH  - Cells, Cultured
MH  - Cholesterol/metabolism
MH  - Cyclooxygenase 2/*metabolism
MH  - Diabetes Mellitus, Type 2/*metabolism
MH  - Endothelial Cells/cytology/metabolism
MH  - Endothelium, Vascular/*metabolism
MH  - Inflammation/metabolism
MH  - Male
MH  - Mice
MH  - NADH, NADPH Oxidoreductases/*metabolism
MH  - NADPH Oxidase 1
MH  - Nitric Oxide Synthase Type III/*metabolism
MH  - RNA, Small Interfering/metabolism
MH  - Superoxides/metabolism
PMC - PMC4518001
EDAT- 2015/06/30 06:00
MHDA- 2016/05/11 06:00
PMCR- 2016/08/01
CRDT- 2015/06/30 06:00
PHST- 2015/06/30 06:00 [entrez]
PHST- 2015/06/30 06:00 [pubmed]
PHST- 2016/05/11 06:00 [medline]
PHST- 2016/08/01 00:00 [pmc-release]
AID - me-14-1313 [pii]
AID - 10.1210/ME.2014-1313 [doi]
PST - ppublish
SO  - Mol Endocrinol. 2015 Aug;29(8):1123-33. doi: 10.1210/ME.2014-1313. Epub 2015 Jun 
      29.