title: Homocysteine induces 3-hydroxy-3-methylglutaryl coenzyme a reductase in vascular endothelial cells: a mechanism for development of atherosclerosis?
abstract: 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.
  
  
  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.
authors.affiliation: Department of Medicine, State University of New York, Stony Brook, NY 11794-8152, USA. hongli888@yahoo.com
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Avalyn
authors.initials: A
authors.lastname: Lewis
authors.forename: Sergey
authors.initials: S
authors.lastname: Brodsky
authors.forename: Robert
authors.initials: R
authors.lastname: Rieger
authors.forename: Charles
authors.initials: C
authors.lastname: Iden
authors.forename: Michael S
authors.initials: MS
authors.lastname: Goligorsky
mesh_terms: D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism*; D051242:Caveolin 1; D022461:Caveolins / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D004790:Enzyme Induction / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply / Q000166:cytology / Q000201:enzymology; D008665:Metalloporphyrins / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D019821:Simvastatin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D017077:Culture Media, Conditioned; D016166:Free Radical Scavengers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008665:Metalloporphyrins; D012333:RNA, Messenger; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D006710:Homocysteine; D009569:Nitric Oxide; D002784:Cholesterol; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases