Objective PERK/eI F2α/CHOP is a major signaling pathway mediating endoplasmic reticulum(ER) stress related with atherosclerosis.Oxidized LDL(ox-LDL) also induces endothelial apoptosis and plays a vital role in the initiation and progression of atherosclerosis.The present study was conducted to explore the regulatory effect of ox-LDL on PERK/e IF2α/CHOP signaling pathway in vascular endothelial cells.Methods The effects of ox-LDL on PERK and p-e IF2α protein expression of primary human umbilical vein endothelial cells(HUVECs) were investigated by Western blot analysis.PERK gene silencing and selective eI F2α phosphatase inhibitor,salubrinal were used to inhibit the process of ox-LDL induced endothelial cell apoptosis,caspase-3 activity,and CHOP mR NA level.Results Ox-LDL treatment significantly increased the expression of PERK,PERK-mediated inactivation of e IF2α phosphorylation,and the expression of CHOP,as well as the caspase-3 activity and apoptosis.The effects of ox-LDL were markedly decreased by knocking down PERK with stable transduction of lentiviral sh RNA or by selective eI F2α phosphatase inhibitor,salubrinal.Conclusion This study provides the first evidence that ox-LDL induces apoptosis in vascular endothelial cells mediated largely via the PERK/eI F2α/CHOP ER-stress pathway.It adds new insights into the molecular mechanisms underlying the pathogenesis and progression of atherosclerosis. 相似文献
[目的]研究木犀草素的分子特性,筛选并鉴定木犀草素抗骨性关节炎(osteoarthritis,OA)的潜在靶点。[方法]通过中药系统药理学数据库及分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,TCMSP)分析木犀草素的药理参数和分子特性;通过Swiss TargetPrediction和药物再定位及药物不良反应预测(predict drug repositioning and adverse drug reaction,DRAR-CPI)软件筛选木犀草素抗OA的潜在靶点;通过人类孟德尔遗传(Online Mendelian Inheritance in Man,OMIM)数据库、比较毒物遗传学数据库(The Comparative Toxicogenomics Database,CTD)和药物靶标数据库(Therapeutic Target Database,TTD)筛选已报道与OA相关的疾病靶点,并与木犀草素潜在靶点进行匹配,确定木犀草素抗OA的靶点,进一步采用分子对接软件对木犀草素抗OA的潜在靶点进行鉴定。[结果]木犀草素口服生物利用率为36.16%,药物相似度为0.25,具有很好的成药性;Swiss TargetPrediction和DRAR-CPI软件共筛选出6个潜在靶点,与OA直接相关的靶点有3个,经分子对接软件鉴定,间质胶原酶1/基质金属蛋白酶1(interstitial collagenase 1/matrix metalloproteinase 1,MMP1)和基质分解素-1/基质金属蛋白酶3(stromelysin-1/matrix metalloproteinase 3,MMP3)为木犀草素抗OA的潜在靶点。[结论]木犀草素可能通过结合MMP1和MMP3,下调其表达量,最终缓解OA的炎症反应。 相似文献