The Inhibition of Insulin-stimulated Proliferation of Vascular Smooth Muscle Cells by Rosiglitazone Is Mediated by the Akt-mTOR-P70S6K Pathway
2
조회
0
다운로드
3
인용
0
참고문헌
키워드
초록
Purpose: Thiazolidinediones (TZDs) are known to inhibit the proliferation of vascular smooth muscle cell (VSMC) by increasing the activity of p27Kip1 and retinoblastoma protein (RB). However, the upstream signaling mechanisms associated with this pathway have not been elucidated. The Akt-mTOR-P70S6 kinase pathway is the central regulator of cell growth and proliferation, and increases cell proliferation by inhibiting the activities of p27Kip1 and retinoblastoma protein (RB). Therefore, we hypothesized in this study that rosiglitazone inhibits VSMC proliferation through the inhibition of the Akt-TOR-P70S6K signaling pathway. Materials and Methods: Rat aortic smooth muscle cells (RAoSMCs) were treated with 10μM of rosiglitazone 24 hours before the addition of insulin as a mitogenic stimulus. Western blot analysis was performed to determine the inhibitory effect of rosiglitazone treatment on the Akt- mTOR-P70S6K signaling pathway. Carotid balloon injury was also performed in Otsuka Long-Evans Tokushima Fatty (OLETF) diabetic rats that were pretreated with 3 mg/kg of rosiglitazone. Results: Western blot analysis demonstrated significant inhibition of activation of p-Akt, p-m-TOR, and p-p70S6K in cells treated with rosiglitazone. The inhibition of the activation of the p-mTOR-p-p70S6K pathway seemed to be mediated by both the upstream PI3K pathway and MEK-ERK complex. Conclusion: The inhibitory effect of rosiglitazone on RAoSMC proliferation in vitro and in vivo is mediated by the inhibition of the Akt-mTOR-P70S6K pathway.
Abstract
Purpose: Thiazolidinediones (TZDs) are known to inhibit the proliferation of vascular smooth muscle cell (VSMC) by increasing the activity of p27Kip1 and retinoblastoma protein (RB). However, the upstream signaling mechanisms associated with this pathway have not been elucidated. The Akt-mTOR-P70S6 kinase pathway is the central regulator of cell growth and proliferation, and increases cell proliferation by inhibiting the activities of p27Kip1 and retinoblastoma protein (RB). Therefore, we hypothesized in this study that rosiglitazone inhibits VSMC proliferation through the inhibition of the Akt-TOR-P70S6K signaling pathway. Materials and Methods: Rat aortic smooth muscle cells (RAoSMCs) were treated with 10μM of rosiglitazone 24 hours before the addition of insulin as a mitogenic stimulus. Western blot analysis was performed to determine the inhibitory effect of rosiglitazone treatment on the Akt- mTOR-P70S6K signaling pathway. Carotid balloon injury was also performed in Otsuka Long-Evans Tokushima Fatty (OLETF) diabetic rats that were pretreated with 3 mg/kg of rosiglitazone. Results: Western blot analysis demonstrated significant inhibition of activation of p-Akt, p-m-TOR, and p-p70S6K in cells treated with rosiglitazone. The inhibition of the activation of the p-mTOR-p-p70S6K pathway seemed to be mediated by both the upstream PI3K pathway and MEK-ERK complex. Conclusion: The inhibitory effect of rosiglitazone on RAoSMC proliferation in vitro and in vivo is mediated by the inhibition of the Akt-mTOR-P70S6K pathway.
참고문헌 (22)
- Law RE, "Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia", J Clin Invest, 98, pp.1897~1905 (1996)
- Jiang C, "PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines", Nature, 391, pp.82~86 (1998)
- Ricote M, "The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation", Nature, 391, pp.79~82 (1998)
- Jackson SM, "Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction", Arterioscler Thromb Vasc Biol, 19, pp.2094~2104 (1999)
- Pasceri V, "Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators", Circulation, 101, pp.235~238 (2000)
- Lehmann JM, "An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma)", J Biol Chem, 270, pp.12953~12956 (1995)
- Bruemmer D, "Thiazolidinedione regulation of smooth muscle cell proliferation", Am J Med, 115(8A), pp.87S~92S (2003)
- Choi D, "Preventative effects of rosiglitazone on restenosis after coronary stent implantation in patients with type 2 diabetes", Diabetes Care, 27, pp.2654~2660 (2004)
- Sehgal SN, "Rapamune (Sirolimus, rapamycin): an overview and mechanism of action", Ther Drug Monit, 17, pp.660~665 (1995)
- Poon M, "Rapamycin inhibits vascular smooth muscle cell migration", J Clin Invest, 98, pp.2277~2283 (1996)
- Martin DE, "The expanding TOR signaling network", Curr Opin Cell Biol, 17, pp.158~166 (2005)
- Proud CG, "The multifaceted role of mTOR in cellular stress responses", DNA Repair (Amst), 3, pp.927~934 (2004)
- Indolfi C, "Effects of balloon injury on neointimal hyperplasia in streptozotocin-induced diabetes and in hyperinsulinemic nondiabetic pancreatic islettransplanted rats", Circulation, 103, pp.2980~2986 (2001)
- Bhandari BK, "Insulin regulation of protein translation repressor 4E-BP1, an eIF4E-binding protein, in renal epithelial cells", Kidney Int, 59, pp.866~875 (2001)
- Hafizi S, "ANG II activates effectors of mTOR via PI3-K signaling in human coronary smooth muscle cells", Am J Physiol Heart Circ Physiol, 287, pp.H1232~H1238 (2004)
- Lee KH, "Antiproliferative mechanisms of raxofelast (IRFI-016) in H2O2-stimulated rat aortic smooth muscle cells", Eur J Pharmacol, 484, pp.119~125 (2004)
- Farese RV, "Insulin-sensitive phospholipid signaling systems and glucose transport. Update II", Exp Biol Med (Maywood), 226, pp.283~295 (2001)
- Taha C, "The insulin signaling pathway", J Membr Biol, 169, pp.1~12 (1999)
- Olefsky JM, "PPAR gamma and the treatment of insulin resistance", Trends Endocrinol Metab, 11, pp.362~368 (2000)
- Kimura N, "A possible linkage between AMPactivated protein kinase (AMPK) and mammaliantarget of rapamycin (mTOR) signalling pathway", Genes Cells, 8, pp.65~79 (2003)
- Inoki K, "TSC2 mediates cellular energy response to control cell growth and survival", Cell, 115, pp.577~590 (2003)
- Marx SO, "Rapamycin- FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells", Circ Res, 76, pp.412~417 (1995)