title: Anti-proliferative effect of rosiglitazone on angiotensin II-induced vascular smooth muscle cell proliferation is mediated by the mTOR pathway.
abstract: VSMC (vascular smooth muscle cell) proliferation contributes significantly to intimal thickening in atherosclerosis, restenosis and venous bypass graft diseases. Ang II (angiotensin II) has been implicated in VSMC proliferation though the activation of multiple growth-promoting signals. Although TZDs (thiazolidinediones) can inhibit VSMC proliferation and reduce Ang II-induced fibrosis, the mechanism underlying the inhibition of VSMC proliferation and fibrosis needs elucidation. We have used primary cultured rat aortic VSMCs and specific antibodies to investigate the inhibitory mechanism of rosiglitazone on Ang II-induced VSMC proliferation. Rosiglitazone treatment significantly inhibited Ang II-induced rat aortic VSMC proliferation in a dose-dependent manner. Western blot analysis showed that rosiglitazone significantly lowered phosphorylated ERK1/2 (extracellular-signal-regulated kinase 1/2), Akt (also known as protein kinase B), mTOR (mammalian target of rapamycin), p70S6K (70 kDa S6 kinase) and 4EBP1 (eukaryotic initiation factor 4E-binding protein) levels in Ang II-treated VSMCs. In addition, PPAR-γ (peroxisome-proliferator-activated receptor γ) mRNA increased significantly and CTGF (connective tissue growth factor), Fn (fibronectin) and Col III (collagen III) levels decreased significantly. The results demonstrate that the rosiglitazone directly inhibits the pro-atherosclerotic effect of Ang II on rat aortic VSMCs. It also attenuates Ang II-induced ECM (extracellular matrix) molecules and CTGF production in rat aortic VSMCs, reducing fibrosis. Importantly, PPAR-γ activation mediates these effects, in part, through the mTOR-p70S6K and -4EBP1 system.
authors: Cardiology Division, Yonsei Cardiovascular Center, Yonsei University Health System, Seoul, South Korea.
authors: Jung-Sun
authors: JS
authors: Kim
authors: Il-Kwon
authors: IK
authors: Kim
authors: Se-Yeon
authors: SY
authors: Lee
authors: Byeong-Wook
authors: BW
authors: Song
authors: Min-Ji
authors: MJ
authors: Cha
authors: Heesang
authors: H
authors: Song
authors: Eunmi
authors: E
authors: Choi
authors: Soyeon
authors: S
authors: Lim
authors: Onju
authors: O
authors: Ham
authors: Yangsoo
authors: Y
authors: Jang
authors: Ki-Chul
authors: KC
authors: Hwang
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000804:Angiotensin II; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases