Published Online
on February 4, 2002

A more recent version of this article appeared on March 5, 2002

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Submitted on September 20, 2001
Revised on December 19, 2001
Accepted on December 21, 2001

Homocysteine Induces 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase in Vascular Endothelial Cells. A Mechanism for Development of Atherosclerosis?

Hong Li MD^*, Avalyn Lewis BS, Sergey Brodsky MD, PhD, Robert Rieger BS, Charles Iden PhD, and Michael S. Goligorsky MD, PhD

From the Departments of Medicine, Physiology, and Biophysics (H.L., S.B., M.S.G.) and Pharmacological Sciences (A.L., R.R., C.I.), State University of New York, Stony Brook, NY.

^* To whom correspondence should be addressed. E-mail: hongli888{at}yahoo.com.

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 (_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 µmol/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.

Key words: endothelium • cholesterol • statins • nitric oxide

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