Homocysteine induces smooth muscle cell proliferation through differential regulation of cyclins A and D1 expression.
The mechanism of homocysteine-induced cell proliferation in human vascular smooth muscle cells (SMCs) remains unclear. We investigated the molecular mechanisms by which homocysteine affects the expression of cyclins A and D1 in human umbilical artery SMCs (HUASMCs). Homocysteine treatment induced proliferation of HUASMCs and increased the expression levels of cyclins A and D1. Knocking down either cyclin A or cyclin D1 by small interfering RNA (siRNA) inhibited homocysteine-induced cell proliferation. Furthermore, treatment with extracellular signal-related kinase (ERK) inhibitor (PD98059) and dominant negative Ras (RasN17) abolished homocysteine-induced cyclin A expression; and treatment with phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002) and mammalian target of rapamycin (mTOR) inhibitor (rapamycin) attenuated the homocysteine-induced cyclin D1 expression. Homocysteine also induced transient phosphorylation of ERK, Akt, and p70 ribosomal S6 kinase (p70S6K). Neutralizing antibody and siRNA for β1 integrin blocked cell proliferation, expression of cyclins A and D1, and phosphorylation of ERK and Akt. In conclusion, homocysteine-induced differential activation of Ras/ERK and PI3K/Akt/p70S6K signaling pathways and consequent expression of cyclins A and D1 are dependent on β1 integrin. Homocysteine may accelerate progression of atherosclerotic lesions by promoting SMC proliferation.
Chiang
Jui-Kun
JK
Department of Family Medicine, Buddhist Dalin Tzu Chi General Hospital, Dalin, Chiayi, Taiwan.
Sung
Mao-Lin
ML
Yu
Hong-Ren
HR
Chang
Hsin-I
HI
Kuo
Hsing-Chun
HC
Tsai
Tzung-Chieh
TC
Yen
Chia-Kuang
CK
Chen
Cheng-Nan
CN
D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019925:Cyclin A / Q000235:genetics* / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000201:enzymology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014469:Umbilical Arteries / Q000166:cytology; D018631:ras Proteins / Q000378:metabolism
D019925:Cyclin A; D019012:Integrin beta1; D006710:Homocysteine; D019938:Cyclin D1; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins