Homocysteine induces connective tissue growth factor expression in vascular smooth muscle cells.
BACKGROUND
Increased homocysteine levels in blood might be an important risk factor for the development of cardiovascular diseases. Connective tissue growth factor (CTGF) was found to be involved in atherosclerotic plaque progression. So far, the possible connection between homocysteine and CTGF has not been studied.


OBJECTIVE
This study was designed to test whether homocysteine could induce CTGF expression in vascular smooth muscle cells (VSMC).


RESULTS
Hyperhomocysteinemia was induced in Sprague-Dawley rats after 4 weeks of a high-methionine diet. CTGF mRNA and protein expression was detected in the aortas isolated from hyperhomocysteinemic rats, but not in the controls. The underlying mechanism of homocysteine-induced CTGF expression was investigated in cultured human umbilical vein smooth muscle cells (HUVSMC). CTGF mRNA expression was induced after treatment with dl-homocysteine (50 micromol L(-1)) for 1 h, which remained at the elevated level for up to 8 h. CTGF protein level increased after homocysteine treatment for 8 h, and the elevated status was maintained for up to 48 h. Several intracellular signals elicited by homocysteine are involved in CTGF synthesis, including protein kinase C (PKC) activation and reactive oxygen species (ROS). Transfection HUVSMCs with a CTGF small interference RNA (siRNA) plasmid, which specifically inhibited the expression of CTGF, decreased extracellular matrix (ECM) accumulation caused by homocysteine.


CONCLUSIONS
Our results demonstrate that homocysteine could increase the expression of CTGF in VSMC both in vivo and in vitro. The novel findings suggest that homocysteine might contribute to accelerated progression of atherosclerotic lesions by inducing CTGF expression.
Liu
X
X
Laboratory of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, China. xiaojingliu67@yahoo.com
Luo
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F
Li
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J
Wu
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W
Li
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L
Chen
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H
D000818:Animals; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D005786:Gene Expression Regulation / Q000187:drug effects; D006710:Homocysteine / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008715:Methionine / Q000008:administration & dosage; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism
C526317:CCN2 protein, human; C526316:CCN2 protein, rat; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D006710:Homocysteine; D055513:Connective Tissue Growth Factor; D008715:Methionine