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J. Lipid Res.
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A more recent version of this article appeared on September 1, 2003

Papers In Press, published online ahead of print June 16, 2003
J. Lipid Res., doi:10.1194/jlr.M300006-JLR200
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Submitted on January 3, 2003
Revised on June 2, 2003
Accepted on June 5, 2003

Ox-LDL induces mitogen-activated protein kinase activation mediated via PI3-kinase/Akt in vascular smooth muscle cells

Ming-Wei Chien, Chin-Sung Chien, Li-Der Hsiao, Ching-Hsuan Lin, and Chuen-Mao Yang

Department of Pharmacology, Chang Gung University, Tao-Yuan, Taipei 3332

Corresponding Author: chuenmao{at}mail.cgu.edu.tw

Oxidized low-density lipoprotein (Ox-LDL) is a risk factor in atherosclerosis and stimulates multiple signaling pathways including activation of phosphatidylinositol 3-kinase (PI3-K)/Akt and p42/p44 mitogen-activate protein kinase (MAPK), which involved in mitogenesis of vascular smooth muscle cells (VSMCs). We therefore investigated the relationship between PI3-K/Akt and p42/p44 MAPK activation and cell proliferation induced by Ox-LDL. Ox-LDL stimulated Akt phosphorylation in a time- and concentration-dependent manner, as determined by Western blot analysis. Phosphorylation of Akt stimulated by Ox-LDL and EGF was attenuated by inhibitors of PI3-K (wortmannin and LY294002) and intracellular Ca2+ chelator (BAPTA/AM) plus EDTA. Pretreatment of VSMCs with pertussis toxin, cholera toxin, and forskolin for 24 h also attenuated the Ox-LDL-stimulated Akt phosphorylation. In addition, pretreatment of VSMCs with wortmannin or LY294002 inhibited Ox-LDL-stimulated p42/p44 MAPK phosphorylation and [3H]thymidine incorporation. Furthermore, treatment with U0126, an inhibitor of MEK1/2, attenuated the p42/p44 MAPK phosphorylation, but no effect on Akt activation in response to Ox-LDL and EGF. Overexpression of p85-DN or Akt-DN mutant attenuated MEK1/2 and p42/p44 MAPK phosphorylation stimulated by Ox-LDL and EGF. These results suggest that the mitogenic effect of Ox-LDL is, at least in part, mediated through activation of PI3-K/Akt/MEK/MAPK pathway in VSMCs. ---Chien, M. W., C. S. Chien, L. D. Hsiao, C. H. Lin and C. M. Yang. Ox-LDL induces mitogen-activated protein kinase activation mediated via PI3-kinase/Akt in vascular smooth muscle cells. J. Lipid Res. 2003, ___:_____-_____.


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