PMID- 16210565
OWN - NLM
STAT- MEDLINE
DCOM- 20060120
LR  - 20231213
IS  - 1524-4636 (Electronic)
IS  - 1079-5642 (Print)
IS  - 1079-5642 (Linking)
VI  - 25
IP  - 12
DP  - 2005 Dec
TI  - Hyperhomocystinemia impairs endothelial function and eNOS activity via PKC 
      activation.
PG  - 2515-21
AB  - OBJECTIVE: A risk factor for cardiovascular disease, hyperhomocystinemia (HHcy), 
      is associated with endothelial dysfunction. In this study, we examined the 
      mechanistic role of HHcy in endothelial dysfunction. METHODS AND RESULTS: Through 
      the use of 2 functional models, aortic rings and intravital video microscopy of 
      the cremaster, we found that arterial relaxation in response to the 
      endothelium-dependent vessel relaxant, acetylcholine or the nitric oxide synthase 
      (NOS) activator (A23187), was significantly impaired in cystathionine 
      beta-synthase null (CBS(-/-)) mice. However, the vascular smooth muscle cell 
      (VSMC) response to the nitric oxide (NO) donor (SNAP) was preserved in CBS(-/-) 
      mice. In addition, superoxide dismutase and catalase failed to restore 
      endothelium-dependent vasodilatation. Endothelial nitric oxide synthase (eNOS) 
      activity was significantly reduced in mouse aortic endothelial cells (MAECs) of 
      CBS(-/-) mice, as well as in Hcy-treated mouse and human aortic endothelial cells 
      (HAECs). Hcy-mediated eNOS inhibition--which was not rescued by adenoviral 
      transduction of superoxide dismutase and glutathione peroxidase, or by 
      tetrahydrobiopterin, sepiapterin, and arginine supplementations in MAEC--was 
      associated with decreased protein expression and increased threonine 495 
      phosphorylation of eNOS in HAECs. Ultimately, a protein kinase C (PKC) inhibitor, 
      GF109203X (GFX), reversed Hcy-mediated eNOS inactivation and threonine 495 
      phosphorylation in HAECs. CONCLUSIONS: These data suggest that HHcy impairs 
      endothelial function and eNOS activity, primarily through PKC activation.
FAU - Jiang, Xiaohua
AU  - Jiang X
AD  - Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Yang, Fan
AU  - Yang F
FAU - Tan, Hongmei
AU  - Tan H
FAU - Liao, Dan
AU  - Liao D
FAU - Bryan, Robert M Jr
AU  - Bryan RM Jr
FAU - Randhawa, Jaspreet K
AU  - Randhawa JK
FAU - Rumbaut, Rolando E
AU  - Rumbaut RE
FAU - Durante, William
AU  - Durante W
FAU - Schafer, Andrew I
AU  - Schafer AI
FAU - Yang, Xiaofeng
AU  - Yang X
FAU - Wang, Hong
AU  - Wang H
LA  - eng
GR  - K02 HL074925/HL/NHLBI NIH HHS/United States
GR  - HL74925/HL/NHLBI NIH HHS/United States
GR  - HL59976/HL/NHLBI NIH HHS/United States
GR  - R01 HL077288/HL/NHLBI NIH HHS/United States
GR  - HL77288/HL/NHLBI NIH HHS/United States
GR  - HL67033/HL/NHLBI NIH HHS/United States
GR  - R01 HL064721/HL/NHLBI NIH HHS/United States
GR  - HL64721/HL/NHLBI NIH HHS/United States
GR  - HL36045/HL/NHLBI NIH HHS/United States
GR  - R01 HL036045/HL/NHLBI NIH HHS/United States
GR  - R01 HL059976/HL/NHLBI NIH HHS/United States
GR  - R01 HL067033/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20051006
PL  - United States
TA  - Arterioscler Thromb Vasc Biol
JT  - Arteriosclerosis, thrombosis, and vascular biology
JID - 9505803
RN  - 0 (Antioxidants)
RN  - 0 (Pterins)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 0 (Biopterins)
RN  - 63CV1GEK3Y (N,N-dimethylarginine)
RN  - 94ZLA3W45F (Arginine)
RN  - CJQ26KO7HP (sepiapterin)
RN  - EC 1.11.1.9 (Glutathione Peroxidase)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 1.14.13.39 (Nos3 protein, mouse)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 4.2.1.22 (Cystathionine beta-Synthase)
RN  - EGX657432I (sapropterin)
RN  - EC 1.11.1.9 (Glutathione Peroxidase GPX1)
SB  - IM
MH  - Animals
MH  - Antioxidants/metabolism/pharmacology
MH  - Aorta, Thoracic/cytology
MH  - Arginine/analogs & derivatives/blood/metabolism/pharmacology
MH  - Biopterins/analogs & derivatives/metabolism/pharmacology
MH  - Cells, Cultured
MH  - Cystathionine beta-Synthase/genetics/metabolism
MH  - Endothelium, Vascular/cytology/*enzymology
MH  - Enzyme Activation/physiology
MH  - Female
MH  - Gene Expression Regulation, Enzymologic
MH  - Glutathione Peroxidase/genetics
MH  - Homocysteine/blood
MH  - Humans
MH  - Hyperhomocysteinemia/genetics/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Mutant Strains
MH  - Nitric Oxide Synthase Type II/genetics/*metabolism
MH  - Nitric Oxide Synthase Type III
MH  - Protein Kinase C/*metabolism
MH  - Pterins/metabolism/pharmacology
MH  - Superoxide Dismutase/genetics
MH  - Vasodilation/physiology
MH  - Glutathione Peroxidase GPX1
PMC - PMC4400833
MID - NIHMS677906
EDAT- 2005/10/08 09:00
MHDA- 2006/01/21 09:00
PMCR- 2015/04/17
CRDT- 2005/10/08 09:00
PHST- 2005/10/08 09:00 [pubmed]
PHST- 2006/01/21 09:00 [medline]
PHST- 2005/10/08 09:00 [entrez]
PHST- 2015/04/17 00:00 [pmc-release]
AID - 01.ATV.0000189559.87328.e4 [pii]
AID - 10.1161/01.ATV.0000189559.87328.e4 [doi]
PST - ppublish
SO  - Arterioscler Thromb Vasc Biol. 2005 Dec;25(12):2515-21. doi: 
      10.1161/01.ATV.0000189559.87328.e4. Epub 2005 Oct 6.