Rosiglitzone suppresses angiotensin II-induced production of KLF5 and cell proliferation in rat vascular smooth muscle cells.
Rosiglitzone suppresses angiotensin II-induced production of KLF5 and cell proliferation in rat vascular smooth muscle cells.
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DOI：
10.1371/journal.pone.0123724
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Niu X
中科院分区：
文献类型：
--
作者：
Gao D;Hao G;Meng Z;Ning N;Yang G;Liu Z;Dong X;Niu X
克鲁ppel样因子（KLF）5可启动血管平滑肌细胞（VSMC）增殖，也参与血管紧张素（Ang）II诱导的血管重塑。罗格列酮对血管重塑的保护作用可能是由于其对VSMC增殖的影响。然而，相关的潜在机制仍不清楚。本研究旨在探讨罗格列酮的抗增殖作用是否通过调节Ang II / KLF5反应来介导。我们发现，在注射Ang II的大鼠主动脉中，血管重塑和KLF5表达显著增加，其靶基因细胞周期蛋白D1过度表达。罗格列酮共同处理可减少这些变化。在生长停滞的VSMC中，过氧化物酶体增殖物激活受体 - γ（PPAR - γ）激动剂（罗格列酮和15d - PGJ2）呈剂量依赖性地抑制Ang II诱导的细胞增殖以及KLF5和细胞周期蛋白D1的表达。此外，这些作用被PPAR - γ拮抗剂GW9662、双酚A二缩水甘油醚和PPAR - γ特异性小干扰RNA减弱。此外，罗格列酮抑制Ang II诱导的蛋白激酶C（PKC）ζ和细胞外信号调节激酶（ERK）1/2的磷酸化以及早期生长反应蛋白（Egr）的激活。总之，在Ang II刺激的VSMC中，罗格列酮可能通过包括降低KLF5表达在内的机制发挥抗增殖作用，并且可能涉及PPAR - γ与PKCζ/ERK1/2/Egr之间的相互作用。这些发现不仅提供了一种此前未被认识的PPAR - γ激动剂抑制VSMC增殖的机制，还为PPAR - γ激活的有益血管效应提供了新的证据。
Krüppel-like factor (KLF) 5, which initiates vascular smooth muscle cell (VSMC) proliferation, also participates in Angiotensin (Ang) II-induced vascular remodeling. The protective effect of rosiglitazone on vascular remodeling may be due to their impact on VSMC proliferation. However, the underlying mechanisms involved remain unclear. This study was designed to investigate whether the antiproliferation effects of rosiglitazone are mediated by regulating Ang II/KLF5 response. We found that, in aortas of Ang II-infused rats, vascular remodeling and KLF5 expression were markedly increased, and its target gene cyclin D1 was overexpressed. Co-treatment with rosiglitazone diminished these changes. In growth-arrested VSMCs, PPAR-γ agonists (rosiglitazone and 15d-PGJ2) dose-dependently inhibited Ang II-induced cell proliferation and expression of KLF5 and cyclin D1. Moreover, these effects were attenuated by the PPAR-γ antagonists GW9662, bisphenol A diglycidyl ether and PPAR-γ specific siRNA. Furthermore, rosiglitazone inhibited Ang II-induced phosphorylation of protein kinase C (PKC) ζ and extracellular signal-regulated kinase (ERK) 1/2 and activation of early growth response protein (Egr). In conclusion, in Ang II-stimulated VSMCs, rosiglitazone might have an antiproliferative effect through mechanisms that include reducing KLF5 expression, and a crosstalk between PPAR-γ and PKCζ/ERK1/2/Egr may be involved in. These findings not only provide a previously unrecognized mechanism by which PPAR-γ agonists inhibit VSMC proliferation, but also document a novel evidence for the beneficial vascular effect of PPAR-γ activation.
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