RAGE通过LKB1和PP2A通路来调节AMPK活性从而介导颈动脉损伤后的血管重构

发布时间：2018-05-04 18:23

本文选题：RAGE + 血管平滑肌细胞　；参考：《浙江大学》2011年博士论文

【摘要】：背景和目的：在动脉粥样硬化,高血压,血管再狭窄等心血管疾病中血管平滑肌细胞(VSMC)增生迁移诱发的新生内膜形成最终会导致动脉狭窄,血栓形成以及梗死。RAGE是一种与糖尿病肾脏和血管并发症相关的跨膜信号受体,并已知能促进血管损伤后血管重构。AMPK是代谢的高敏调节器,能调节细胞分化。AMPK激活能抑制VSMC增生和血管重构,并有抗炎效应。AMPK的调节包括上游激酶的磷酸化和蛋白激酶的磷酸化抑制。LKB1,一种丝／苏氨酸蛋白激酶,是激活AMPK的主要上游底物之一,最初被确认为一种肿瘤抑制因子。蛋白激酶2A (PP2A)通过去磷酸化AMPKα而灭活AMPK。在此,我们假设RAGE是通过调节AMPK活性诱发血管重构,并且是经过LKB1和PP2A这两种信号通路。方法和结果：我们选择了一些已知在血管疾病中表达增高和调节代谢、动脉粥样硬化血管疾病的RAGE配体来研究(S100钙粒蛋白如S100A11,糖化白蛋白)。6-8周大小的WT和Rage-/-小鼠被用于做颈动脉结扎模型(CAL)。S100A11和糖化白蛋白对VSMC具有抑制AMPK活性,并且诱导其增生和迁移的作用,该作用能被RAGE缺失或优先激活AMPK所抑制。在RNA干涉试验中我们发现LKB1和PP2A对于VSMC的AMPK活性起了关键调节作用。RAGE和S100A11在颈动脉结扎后表达增高,而原位的AMPK活性,磷酸化LKB1和磷酸化PP2A则表达减少。最后,CAL后Rage-/-小鼠的新生内膜形成明显较WT组减轻,同时western blot和免疫组化染色结果显示Rage-/-原位AMPK活性增高,磷酸化LKB1和磷酸化PP2A表达也增加。结论：RAGE通过降低AMPK-磷酸化LKB1活性和增加AMPK-去磷酸化PP2A活性来抑制AMPK激活,从而促进动脉损伤后血管重构。增加AMPK活性也许会成为血管重构性疾病的一个新的治疗靶向。
[Abstract]:Background & AIM: in cardiovascular diseases such as atherosclerosis, hypertension, vascular restenosis and other cardiovascular diseases, vascular smooth muscle cells (VSMCMC) proliferation and migration induce neointimal formation that ultimately leads to arterial stenosis. Thrombosis and infarction. Rage is a transmembrane signal receptor associated with renal and vascular complications in diabetic patients, and has been known to promote vascular remodeling after vascular injury. AMPK is a metabolic regulator for Gao Min. Regulation of cell differentiation. AMPK activation inhibits VSMC proliferation and vascular remodeling, and has anti-inflammatory effects. The regulation of AMPK includes phosphorylation of upstream kinases and phosphorylation inhibition of protein kinases. LKB1, a silk / threonine protein kinase. Is one of the main upstream substrates that activate AMPK and was initially identified as a tumor suppressor. Protein kinase 2A (PP2A) inactivated AMPK by dephosphorylation of AMPK 伪. We assume that RAGE induces vascular remodeling by regulating the activity of AMPK and goes through two signaling pathways, LKB1 and PP2A. Methods and results: we selected some of the known increases in expression and regulation of metabolism in vascular diseases. RAGE ligands of atherosclerotic vascular diseases were used to study the inhibitory activity of S100 calmodulin such as S100A11, glycosylated albumin, WT and Rage-r-mice for carotid artery ligation model (CAL, S100A11) and glycosylated albumin (Albumin) in inhibiting AMPK activity on VSMC. It also induces proliferation and migration, which can be inhibited by RAGE deletion or preferential activation of AMPK. In RNA interference test, we found that LKB1 and PP2A played a key role in regulating the AMPK activity of VSMC. Rage and S100A11 expression increased after carotid artery ligation, while in situ AMPK activity, phosphorylated LKB1 and phosphorylated PP2A decreased. At last, the neointimal formation of Rage-r-mice after CAL was much less than that of WT group. Meanwhile, western blot and immunohistochemical staining showed that the activity of Rage-r-in-situ AMPK was increased, and the expression of phosphorylated LKB1 and phosphorylated PP2A was also increased. Conclusion by decreasing the activity of AMPK- phosphorylated LKB1 and increasing the activity of AMPK- dephosphorylated PP2A, the activation of AMPK is inhibited by% rage, which can promote vascular remodeling after arterial injury. Increasing AMPK activity may be a new therapeutic target for vascular remodeling diseases.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2011
【分类号】：R363

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