PMID- 11877351
OWN - NLM
STAT- MEDLINE
DCOM- 20020318
LR  - 20220310
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Linking)
VI  - 105
IP  - 9
DP  - 2002 Mar 5
TI  - Homocysteine induces 3-hydroxy-3-methylglutaryl coenzyme a reductase in vascular 
      endothelial cells: a mechanism for development of atherosclerosis?
PG  - 1037-43
AB  - BACKGROUND: It has been established that hyperhomocyst(e)inemia (HHCy) is an 
      independent and graded risk factor for atherosclerosis, although the molecular 
      link to the atherosclerotic process remains obscure. METHODS AND RESULTS: 
      Screening human umbilical vein endothelial cells (HUVECs) with complementary DNA 
      microarray for the gene expression modified by homocysteine (Hcy) revealed that 
      3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) was upregulated. This 
      effect was confirmed using quantitative reverse transcriptase-polymerase chain 
      reaction. Actinomycin D studies revealed that Hcy stabilized HMGCR mRNA 
      (tau(1/2), 9.5 +/- 1.0 versus 5.0 +/- 0.2 hours). Expression of immunodetectable 
      HMGCR in both HUVECs and renal microvascular endothelial cells was increased in 
      Hcy-treated cells in association with the increased abundance of caveolin. 
      Application of a cell-permeable superoxide dismutase mimetic, Mn-TBAP, reversed 
      the Hcy-induced expression of HMGCR. Additional biochemical analysis of the 
      abundance of total cellular cholesterol showed that 0, 20, 50, and 100 micromol/L 
      Hcy resulted in 22.2 +/- 7.3%, 39.5 +/- 1.2%, and 50.4 +/- 6.8% increase, 
      respectively. Gas chromatography mass spectrometry analysis of extracted 
      cholesterol from Hcy-treated HUVECs and from the culture medium showed 17.8 +/- 
      5.2% and 24.0 +/- 14.5% increases, respectively. Application of simvastatin to 
      Hcy-treated cells reduced cellular cholesterol and prevented Hcy-induced 
      suppression of NO production by HUVECs in a dose-dependent manner. CONCLUSIONS: 
      Using a cDNA microarray, the data disclosed an unexpected link between Hcy and 
      cholesterol dysregulation based on the finding of increased abundance of HMGCR 
      mRNA and protein in endothelial cells, demonstrated the possible role of 
      Hcy-induced oxidative stress in this response, and revealed the improvement of 
      endothelial NO production in Hcy-treated HUVECs by statins. Collectively, these 
      findings may provide a solid explanation for the observed proatherogenic effect 
      of HHcy.
FAU - Li, Hong
AU  - Li H
AD  - Department of Medicine, State University of New York, Stony Brook, NY 11794-8152, 
      USA. hongli888@yahoo.com
FAU - Lewis, Avalyn
AU  - Lewis A
FAU - Brodsky, Sergey
AU  - Brodsky S
FAU - Rieger, Robert
AU  - Rieger R
FAU - Iden, Charles
AU  - Iden C
FAU - Goligorsky, Michael S
AU  - Goligorsky MS
LA  - eng
GR  - CH82902/CH/OID CDC HHS/United States
GR  - DK45462/DK/NIDDK NIH HHS/United States
GR  - DK52783/DK/NIDDK NIH HHS/United States
GR  - DK54602/DK/NIDDK NIH HHS/United States
GR  - T32DK07521-14/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (CAV1 protein, human)
RN  - 0 (Caveolin 1)
RN  - 0 (Caveolins)
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (Free Radical Scavengers)
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (Metalloporphyrins)
RN  - 0 (RNA, Messenger)
RN  - 0 (manganese(III)-tetrakis(4-benzoic acid)porphyrin)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - AGG2FN16EV (Simvastatin)
RN  - EC 1.1.1.- (Hydroxymethylglutaryl CoA Reductases)
SB  - IM
MH  - Arteriosclerosis/etiology/*metabolism
MH  - Caveolin 1
MH  - Caveolins/metabolism
MH  - Cells, Cultured
MH  - Cholesterol/metabolism
MH  - Culture Media, Conditioned/chemistry/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Endothelium, Vascular/cytology/*drug effects/*enzymology
MH  - Enzyme Induction/drug effects
MH  - Free Radical Scavengers/pharmacology
MH  - Gene Expression/drug effects
MH  - Homocysteine/*pharmacology
MH  - Humans
MH  - Hydroxymethylglutaryl CoA Reductases/genetics/*metabolism
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology
MH  - Kidney/blood supply/cytology/enzymology
MH  - Metalloporphyrins/pharmacology
MH  - Nitric Oxide/metabolism
MH  - Oligonucleotide Array Sequence Analysis
MH  - RNA Stability/drug effects
MH  - RNA, Messenger/metabolism
MH  - Risk Factors
MH  - Simvastatin/pharmacology
MH  - Up-Regulation/drug effects
EDAT- 2002/03/06 10:00
MHDA- 2002/03/19 10:01
CRDT- 2002/03/06 10:00
PHST- 2002/03/06 10:00 [pubmed]
PHST- 2002/03/19 10:01 [medline]
PHST- 2002/03/06 10:00 [entrez]
AID - 10.1161/hc0902.104713 [doi]
PST - ppublish
SO  - Circulation. 2002 Mar 5;105(9):1037-43. doi: 10.1161/hc0902.104713.