Heat shock protein 27 (Hsp27) is a putative biomarker and therapeutic target in atherosclerosis. This study was to explore the potential mechanisms underlying Hsp27 effects on ATP-binding cassette transporter A1 (ABCA1) expression and cellular cholesterol efflux. THP-1 macrophage-derived foam cells were infected with adenovirus to express wild-type Hsp27, hyper-phosphorylated Hsp27 mimic (3D Hsp27), antisense Hsp27 or hypo-phosphorylated Hsp27 mimic (3A Hsp27). Wild-type and 3D Hsp27 were found to up-regulate ABCA1 mRNA and protein expression and increase cholesterol efflux from cells. Expression of antisense or 3A Hsp27 suppressed the expression of ABCA1 and cholesterol efflux. Furthermore, over-expression of wild-type and 3D Hsp27 significantly increased the levels of phosphorylated specificity protein 1 (Sp1), protein kinase C ζ (PKCζ) and phosphatidylinositol 3-kinase (PI3K). In addition, the up-regulation of ABCA1 expression and cholesterol efflux induced by 3D Hsp27 was suppressed by inhibition of Sp1, PKCζ and PI3K with specific kinase inhibitors. Taken together, our results revealed that Hsp27 may up-regulate the expression of ABCA1 and promotes cholesterol efflux through activation of the PI3K/PKCζ/Sp1 signal pathway in THP-1 macrophage-derived foam cells. Our findings may partly explain the mechanisms underlying the anti-atherogenic effect of Hsp27.

Heat shock protein 27 (Hsp27) is a putative biomarker and therapeutic target in atherosclerosis. This study was to explore the potential mechanisms underlying Hsp27 effects on ATP-binding cassette transporter A1 (ABCA1) expression and cellular cholesterol efflux. THP-1 macrophage-derived foam cells were infected with adenovirus to express wild-type Hsp27, hyper-phosphorylated Hsp27 mimic (3D Hsp27), antisense Hsp27 or hypo-phosphorylated Hsp27 mimic (3A Hsp27). Wild-type and 3D Hsp27 were found to up-regulate ABCA1 mRNA and protein expression and increase cholesterol efflux from cells. Expression of antisense or 3A Hsp27 suppressed the expression of ABCA1 and cholesterol efflux. Furthermore, over-expression of wild-type and 3D Hsp27 significantly increased the levels of phosphorylated specificity protein 1 (Sp1), protein kinase C ζ (PKCζ) and phosphatidylinositol 3-kinase (PI3K). In addition, the up-regulation of ABCA1 expression and cholesterol efflux induced by 3D Hsp27 was suppressed by inhibition of Sp1, PKCζ and PI3K with specific kinase inhibitors. Taken together, our results revealed that Hsp27 may up-regulate the expression of ABCA1 and promotes cholesterol efflux through activation of the PI3K/PKCζ/Sp1 signal pathway in THP-1 macrophage-derived foam cells. Our findings may partly explain the mechanisms underlying the anti-atherogenic effect of Hsp27.

Heat shock protein 27 (Hsp27) is a putative biomarker and therapeutic target in atherosclerosis. This study was to explore the potential mechanisms underlying Hsp27 effects on ATP-binding cassette transporter Al (ABCA1) expression and cellular cholesterol efflux. THP-1 macrophage-derived foam cells were infected with adenovirus to express wild-type Hsp27, hyper-phosphorylated Hsp27 mimic (3D Hsp27), antisense Hsp27 or hypophosphorylated Hsp27 mimic (3A Hsp27). Wild-type and 3D Hsp27 were found to up-regulate ABCA1 mRNA and protein expression and increase cholesterol efflux from cells. Expression of antisense or 3A Hsp27 suppressed the expression of ABCA1 and cholesterol efflux. Furthermore, over-expression of wild-type and 3D Hsp27 significantly increased the levels of phosphorylated specificity protein 1 (Spl), protein kinase C zeta(PKC zeta and phosphatidylinositol 3-kinase (PI3K). In addition, the up-regulation of ABCA1 expression and cholesterol efflux induced by 3D Hsp27 was suppressed by inhibition of Spl, PKC zeta and PI3K with specific kinase inhibitors. Taken together, our results revealed that Hsp27 may up-regulate the expression of ABCA1 and promotes cholesterol efflux through activation of the PI3K/PKC zeta/Sp1 signal pathway in THP-1 macrophage-derived foam cells. Our findings may partly explain the mechanisms underlying the anti-atherogenic effect of Hsp27.

目的:观察miR-146a对泡沫细胞内胆固醇水平的影响,探讨TLR4-ACAT1信号通路在miR-146a调控胆固醇酯中的作用.方法:转染miR-146a mimic和Inhibitor,采用HPLC观察总胆固醇、胆固醇酯和游离胆固醇的变化;qPCR和Western-blot法检测TLR4和ACAT1 mRNA和蛋白的变化.结果:TLR4是miR-146a的一个靶基因,miR-146a通过调控TLR4-ACAT1信号通路,抑制细胞内游离胆固醇向胆固醇酯的转化,减少巨噬细胞内的胆固醇酯含量,减少泡沫细胞的形成.结论:miR-146a通过调控TLR4-ACAT1信号通路,抑制胆固醇酯的形成和泡沫细胞的形成,是动脉粥样硬化防治的重要靶点.

As a transcription auxiliary inhibitor,receptor-interacting protein 140(RIP140) is involved in the regulation of metabolism in human body.Once combined with nuclear receptor,RIP140 can negatively regulate the transcription of target genes within a variety of metabolic organizations include the adipose tissue,muscle tissue,cardiac muscle and liver.When silenced,on the contrary,RIP140 will have an influence on glycolysis,triglyceride metabolism,the tricarboxylic acid cycle,fatty acid β oxidation,inflammatory factor expression,the body clock changes,etc.Therefore RIP140 promises to be a candidate target site for the treatment of metabolic syndrome.

Apelin has an antiatherogenic function through activating protein kinase C (PKC) to initiate a series of cellular signaling pathways. PKC phosphorylates and stabilizes ATP-binding cassette transporter A1 (ABCA1) through inhibiting its degradation mediated by calpain. Thus, in the present study, we investigated whether apelin-13 affects expression of ABCA1 through PKC signaling. The results showed that apelin-13 dramatically increased cholesterol efflux from THP-1 macrophage-derived foam cells and reduced cellular cholesterol levels. ABCA1 protein but not mRNA levels were dramatically increased by apelin-13, and calpain-induced degradation of ABCA1 and calpain activity were suppressed with treatment of apelin-13. However, the effects of apelin-13 on ABCA1 protein expression, cellular cholesterol efflux and calpain activity were abolished by depletion of PKCα, suggesting the potential important role of PKCα. In addition, apelin-13 was shown to phosphorylate serine residues in ABCA1 through the PKCα pathway. Thus, apelin-13 appears to activate PKCα, phosphorylate ABCA1 and inhibit calpain-mediated proteolysis, thereby promoting cholesterol efflux and reducing foam cell formation. Our study herein described a possible mechanism for understanding the antiatherogenic effects of apelin on attenuating the progression of atherosclerosis.

<正>目的:探讨miR-27a/b对ABCA1及其介导的胆固醇流出的影响。方法:萤光素酶报告基因检测miR-27a/b与ABCA1的结合情况;体外培养THP-1细胞、RAW 264.7细胞和HepG细胞,将miR-27a/b mimics或miR-27a/b inhibitor转染入细

目的本实验通过高脂饮食建立早期高脂血症兔模型,观察普罗布考对胆固醇相关转运体以及炎症因子的影响。方法新西兰白兔36只,雄雌不拘,采用数字表法随机分为基础组(n=9)、基础+普罗布考组(每只77 mg/d,n=9)、高脂组(n=9)和高脂+普罗布考组(每只77 mg/d,n=9)。40天后观察普罗布考对血脂的影响;HE染色观察普罗布考对各组新西兰白兔腹主动脉斑块形成的影响;油红O染色观察普罗布考对各组新西兰白兔肝脏脂质蓄积的影响;定量PCR测定普罗布考对新西兰白兔腹主动脉、肝脏和小肠中胆固醇相关转运体基因表达的影响;Western blot以及免疫组化测定普罗布考对新西兰白兔腹主动脉、肝脏、小肠内胆固醇相关转运蛋白表达的影响;ELISA方法测定普罗布考对炎症因子的影响。结果与基础组相比,高脂组免血清总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、甘油三酯(TG)水平均明显升高;与高脂组比较,高脂+普罗布考组免血清TC、LDL-C、HDL-C、TG水平均明显下降;高脂组中有动脉斑块形成,肝脏脂质蓄积增多;高脂+普罗布考组中,普罗布考明显抑制斑块的形成,减少肝脏脂质蓄积;普罗布考促进肝脏中ABCG1和SR-BI蛋白及其mRNA的表达,抑制ABCA1蛋白及其mRNA的表达,对SR-A和CD36的表达没有影响;普罗布考抑制炎症因子如IL-6、MCP-1、MCSF、VCAM-1、TNF-α的表达。结论普罗布考抑制ABCA1和炎症因子的表达,促进ABCG1和SR-B1的表达。