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(Circulation Research. 2003;92:1115.)
© 2003 American Heart Association, Inc.

Molecular Medicine

Phosphatidylinositol 3-Kinase and Calcium-Activated Transcription Pathways Are Required for VLDL-Induced Smooth Muscle Cell Proliferation

Larissa Lipskaia, Marie-Luce Pourci, Claudine Deloménie, Laurent Combettes, Dominique Goudounèche, Jean-Louis Paul, Thierry Capiod, Anne-Marie Lompré

From INSERM U446 (L.L., C.D., A.-M.L.), Laboratoire de Biochimie Appliquée (M.-L.P., D.G., J.-L.P.) and IFR-75: Institut de signalisation et innovation thérapeutique, Faculté de Pharmacie, Châtenay-Malabry, France; and INSERM U442, IFR: Signalisation cellulaire (L.C., T.C.), Faculté des Sciences Bâtiment 443, Orsay, France.

Correspondence to Anne-Marie Lompré, INSERM U446/IFR-75, Institut de signalisation et innovation thérapeutique, Faculté de Pharmacie, Tour D4, 5 rue JB Clément, 92296 Châtenay-Malabry, France. E-mail anne-marie.lompre{at}egm.u-psud.fr

Little is known regarding the molecular mechanisms of atherogenicity of triglyceride-rich lipoproteins such as very low-density lipoproteins (VLDLs). We examined the effect of VLDL on proliferation of rat aortic smooth muscle cells, intracellular Ca²⁺ handling, and activity of cAMP-responsive element binding protein (CREB) and nuclear factor of activated T cells (NFAT) transcription factors. VLDL, isolated from human serum, dose- and time-dependently promoted proliferation. After 4 hours of exposure to VLDL (0.15 g/L proteins), the caffeine-induced Ca²⁺ release was inhibited and the IP3-sensitive Ca²⁺ release induced by ATP (10 µmol/L) was markedly prolonged. In quiescent cells, CREB was phosphorylated (pCREB) and NFAT was present in the cytosol, whereas in cells exposed to VLDL for 4 to 24 hours, pCREB disappeared and NFAT was translocated to the nucleus. VLDL-induced NFAT translocation and proliferation were blocked by cyclosporin A and LY294002 involving calcineurin and phosphatidylinositol 3-kinase (PI3K) pathways. Indeed, VLDLs rapidly phosphorylate protein kinase B and glycogen synthase kinase-3ß in a PI3K-dependent way. These results provide the first evidence that VLDLs induce smooth muscle cell proliferation by activating the PI3K pathway and nuclear NFAT translocation. Blockade of the Ca²⁺-induced Ca²⁺ release mechanism and dephosphorylation of pCREB contribute but were not sufficient to induce a proliferating phenotype.

Key Words: vascular disease • smooth muscle • calcium signaling • transcription factors • lipoproteins

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