Resveratrol inhibits the mTOR mitogenic signaling evoked by oxidized LDL in smooth muscle cells.
OBJECTIVE
Smooth muscle cell (SMC) proliferation is a major feature in atherosclerosis, since it contributes to the formation of the fibrous cap, thus to plaque stability, but also to arterial stenosis and post-angioplasty restenosis. Among the various mitogenic signaling pathways involved in SMC proliferation, the mTOR pathway regulates both the cell cycle and cell growth. Resveratrol, a polyphenolic compound from grapes and red wine, has potential anti-atherogenic and anti-cancer properties. This work was designed to investigate the activation of the mTOR pathway by the proatherogenic oxidized LDL (oxLDL) in SMC, and the potential inhibitory effect of resveratrol.


RESULTS
mTOR and its downstream target p70S6 kinase are phosphorylated and activated by mitogenic concentrations of oxLDL (50 microg/ml), and are involved in SMC proliferation, as assessed by the inhibitory effect of the mTOR inhibitor rapamycin. The activation of mTOR signaling by oxLDL, requires the upstream activation of PI3K and Akt, as assessed by the inhibitory effect of the PI3K inhibitor Ly294002 on mTOR activation and DNA synthesis. Resveratrol blocked the oxLDL-induced phosphorylation and activation of the PI3K/Akt/mTOR/p70S6K pathway and strongly inhibited both the DNA synthesis and proliferation of SMC. This activity is independent of the anti-oxidant effect and of AMPK activation by resveratrol.


CONCLUSIONS
These data indicate that the mTOR pathway is activated by oxLDL via PI3K/PDK1/Akt, and is required for SMC proliferation. Resveratrol blocks specifically this pathway, thereby inhibiting oxLDL-induced SMC proliferation. These data highlight a new property for resveratrol that could contribute to the general anti-atherogenic properties of this polyphenol.
Brito
Paula M
PM
Laboratory of Biochemistry, Faculty of Pharmacy, and Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal.
Devillard
Raphaël
R
Nègre-Salvayre
Anne
A
Almeida
Leonor M
LM
Dinis
Teresa C P
TC
Salvayre
Robert
R
Augé
Nathalie
N
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy; D049109:Cell Proliferation; D005419:Flavonoids / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010636:Phenols / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D059808:Polyphenols; D011494:Protein Kinases / Q000378:metabolism*; D011817:Rabbits; D000077185:Resveratrol; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
D020533:Angiogenesis Inhibitors; D000975:Antioxidants; D005419:Flavonoids; D008077:Lipoproteins, LDL; D010636:Phenols; D019869:Phosphatidylinositol 3-Kinases; D059808:Polyphenols; D011494:Protein Kinases; D000077185:Resveratrol; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D013267:Stilbenes; D058570:TOR Serine-Threonine Kinases; C099252:oxidized low density lipoprotein; C546842:MTOR protein, human