Anti-proliferative effect of rosiglitazone on angiotensin II-induced vascular smooth muscle cell proliferation is mediated by the mTOR pathway
Anti-proliferative effect of rosiglitazone on angiotensin II-induced vascular smooth muscle cell proliferation is mediated by the mTOR pathway
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DOI：
10.1042/cbi20100524
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发表时间：
2012-03-01
影响因子：
3.9
通讯作者：
Hwang, Ki-Chul
中科院分区：
文献类型：
--
作者：
Kim, Jung-Sun;Kim, Il-Kwon;Hwang, Ki-Chul
血管平滑肌细胞（VSMC）的增殖对动脉粥样硬化、再狭窄和静脉旁路移植疾病的内膜增厚有重要作用。Ang II（血管紧张素II）通过激活多种促生长信号参与VSMC增殖。虽然TZDs（噻唑烷二酮）可以抑制VSMC增殖，减少Ang ii诱导的纤维化，但抑制VSMC增殖和纤维化的机制有待阐明。我们采用原代培养的大鼠主动脉VSMC和特异性抗体，研究罗格列酮对angii诱导的VSMC增殖的抑制机制。罗格列酮治疗显著抑制angii诱导的大鼠主动脉VSMC增殖，且呈剂量依赖性。Western blot分析显示，在angii处理的VSMCs中，rosiglitazone显著降低磷酸化的ERK1/2（细胞外信号调节激酶1/2）、Akt（也称为蛋白激酶B）、mTOR（哺乳动物雷帕霉素靶蛋白）、p70S6K （70 kDa S6激酶）和4EBP1（真核起始因子4e结合蛋白）水平。ppar - γ（过氧化物酶体增殖物激活受体γ） mRNA显著升高，CTGF（结缔组织生长因子）、Fn（纤维连接蛋白）和Col III（胶原蛋白III）水平显著降低。结果表明，罗格列酮直接抑制Ang II对大鼠主动脉VSMCs的促动脉粥样硬化作用。它还能减弱大鼠主动脉VSMCs中Ang ii诱导的ECM（细胞外基质）分子和CTGF的产生，减少纤维化。重要的是，ppar - γ激活部分通过mTOR-p70S6K和-4EBP1系统介导这些作用。
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-gamma (peroxisome-proliferator-activated receptor gamma) 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-gamma activation mediates these effects, in part, through the mTOR-p70S6K and -4EBP1 system.