[1]王旭,陈雪,孙梦姣,等.SIRT1激动剂通过降低ACAT1表达抑制平滑肌泡沫细胞形成[J].第三军医大学学报,2017,39(09):546-851.
 Wang Xu,Chen Xue,Sun Mengjiao,et al.SIRT1 agonist inhibits smooth muscle foam cell formation by decreasing ACAT1 expression[J].J Third Mil Med Univ,2017,39(09):546-851.
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SIRT1激动剂通过降低ACAT1表达抑制平滑肌泡沫细胞形成(/HTML )
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《第三军医大学学报》[ISSN:1000-5404/CN:51-1095/R]

卷:
39卷
期数:
2017年第09期
页码:
546-851
栏目:
基础医学
出版日期:
2017-05-15

文章信息/Info

Title:
SIRT1 agonist inhibits smooth muscle foam cell formation by decreasing ACAT1 expression
作者:
王旭陈雪孙梦姣张明杰郭露朱洁李敬诚张莉莉
第三军医大学大坪医院野战外科研究所神经内科;成都军区总医院神经内科
Author(s):
Wang Xu Chen Xue Sun Mengjiao Zhang Mingjie Guo Lu Zhu Jie Li Jingcheng Zhang Lili

Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042; Department of Neurology, General Hospital of Chengdu Military Command, Chengdu, Sichuan Province, 610083, China

关键词:
泡沫细胞血管平滑肌细胞沉默信息调节因子1酰基辅酶A:胆固醇酰基转移酶1氧化型低密度脂蛋白过氧化物酶体增殖物激活受体&gamma
Keywords:
foam cells vascular smooth muscle cell silent information regulation 2 homolog-1 A-cholesterol acyltransferase 1 oxidized low density lipoprotein peroxisome proliferator-activated receptor gamma
分类号:
R322.12; R329.24; R392.32
文献标志码:
A
摘要:

目的      探讨沉默信息调节因子1(silent mating type information regulation 2 homolog-1,SIRT1)对氧化型低密度脂蛋白(oxidized low density lipoprotein,ox-LDL)诱导的血管平滑肌细胞(vascular smooth muscle cell,VSMC)泡沫化的作用和相关的分子机制。方法      用组织贴块法体外培养原代VSMC,用80 μg/mL ox-LDL刺激VSMC诱导泡沫细胞形成。检测SIRT1在ox-LDL刺激不同时间(24、48、72 h)的表达变化。SIRT1的活性调控分别应用SIRT1激动剂(SRT1720,SRT,1 μmol/L)和抑制剂(nicotinamide,Nic,100 μmol/L)进行干预。干预24 h后采用Western blot检测VSMC过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptor γ,PPARγ)、酰基辅酶A:胆固醇酰基转移酶1(A-cholesterol acyltransferase 1,ACAT1)的蛋白表达,干预48 h后采用油红O染色检测细胞内脂质沉积和泡沫细胞形成情况。应用PPARγ激动剂(Rosiglitazone,RSG,50 μmol/L)和抑制剂(GW9662,10 μmol/L)调控PPARγ的表达,Western blot检测VSMC中ACAT1的表达。结果       ①oxLDL诱导的VSMC泡沫细胞中,SIRT1蛋白表达在48 h降低约47%(P<0.01);油红O染色显示,SRT可以抑制VSMC泡沫细胞形成,而Nic可逆转SRT的抑制作用;②oxLDL诱导的VSMC泡沫细胞中ACAT1的表达显著增加[(2.77±0.70),P<0.01],SIRT1激动剂SRT可显著抑制ACAT1的表达[(0.90±0.27),P<0.01],而SIRT1抑制剂Nic可阻断这一作用,升高ACAT1的表达[(2.25±0.37),P<0.05];③oxLDL诱导的VSMC泡沫细胞中PPARγ的表达减少[(0.73±0.12),P<0.05],SIRT1激动剂SRT可上调VSMC中PPARγ的表达[(0.98±0.16),P<0.05],SIRT1抑制剂Nic抑制PPARγ的表达[(0.47±0.13),P<0.01];④PPARγ激动剂RSG可抑制ACAT1的表达[(0.73±009),P<0.01],而PPARγ抑制剂GW9662则上调ACAT1表达[(1.68±0.09),P<0.01]。结论      SIRT1通过上调VSMC中PPARγ表达而抑制ACAT1表达,从而抑制oxLDL诱导的VSMC泡沫样变。

Abstract:

Objective      To determine the effect of silent information regulation 2 homolog-1 (SIRT1) on foam cell formation in vascular smooth muscle cell (VSMC) after the inducement of oxidized low density lipoprotein (ox-LDL) and investigate the underlying mechanisms. Methods      Primary VSMC were isolated from the aorta of male C57BL/6J mice and identified by immunofluorescence staining. The VSMC-derived foam cell formation was induced by the stimulation of 80 μg/mL ox-LDL for 24, 48 or 72 h. The expression profile of SIRT1 was measured in the process of foam cell formation. SIRT1 agonist SRT1720 (SRT, 1 μmol/L) and its antagonist nicotinamide (Nic, 100 μmol/L) were used as well. Western blotting was employed to measure the protein expression levels of peroxisome proliferator-activated receptor gamma (PPARγ) and acyl-coenzyme a: A-cholesterol acyltransferase 1 (ACAT1). Oil red O staining was used to detect intracellular lipid deposition and foam cell formation. PPARγ agonist rosiglitazone (RSG, 50 μmol/L) and its inhibitor GW9662 (10 μmol/L) were used to manipulate the activity of PPARγ, and their effects on the expression of ACAT1 were detected by Western blotting. Results      ①The expression of SIRT1 in VSMC-derived foam cells was reduced approximately by 47% after 48 hours’ ox-LDL incubation (P<0.01). Oil red O staining showed that SRT+ox-LDL treatment inhibited the formation of VSMC-derived foam cells, while the stimulation of SIRT1 antagonist Nic reversed such effect. ②The expression level of ACAT1 was enhanced in the VSMC-derived foam cells (2.77±0.70, P<0.01), which could be counteracted by SRT (0.90±0.27, P<0.01). However, Nic stimulation resulted in block in the inhibition and enhanced the expression of ACAT1 (2.25±0.37, P<0.05). ③The expression of PPARγ was decreased in the VSMC after ox-LDL stimulation (0.73±0.09, P<0.01). SIRT1 agonist SRT significantly up-regulated the expression (0.98±0.16, P<0.05), while Nic down-regulated (0.47±0.13, P<0.01). ④PPARγ agonist RSG suppressed the expression of ACAT1 in VSMC-derived foam cells (0.73±0.09, P<0.01), while the inhibitor GW9662 increased the expression (1.68±0.09, P<0.01). Conclusion      SIRT1 inhibits the expression of ACAT1 induced by ox-LDL through up-regulating PPARγ, and thus ultimately suppresses the foam cell formation in VSMC.

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更新日期/Last Update: 2017-05-05