Estudios científicos
Resveratrol inhibits the mTOR mitogenic signaling evoked by oxidized LDL in smooth muscle cells
Abstract:
OBJECTIVES: 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. CONCLUSION: 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.
Comentarios divulgativos:
La proliferación de las células musculares lisas (SMC) es una característica importante de la aterosclerosis, ya que contribuye a la formación de la capa fibrosa, con lo que no solo detiene la estabilidad de la placa, sino también la estenosis arterial y reestenosis después de la angioplastia. Entre las distintas vías de señalización mitogénica implicadas en la proliferación de SMC, la vía mTOR regula tanto el ciclo celular como el crecimiento celular. El resveratrol, un compuesto polifenólico de la uva y el vino tinto, muestra un potencial anticancerígeno y antiaterogénico. En este testudio se investigó la activación de la vía mTOR por el compuesto proaterogénico: LDL oxidado (LDLox) en SMC, y el posible efecto inhibitorio del resveratrol.
Estos datos indican que la vía de mTOR se activa a través de oxLDL PI3K/PDK1/Akt, y es necesario para la proliferación de SMC. El resveratrol bloquea específicamente esta vía, con lo que la inhibición de la proliferación inducide oxLDL SMC. Estos datos ponen de manifiesto una nueva propiedad del resveratrol que puede contribuir a las propiedades anti-aterogénicas generales de este polifenol.
