摘要
前蛋白转化酶枯草溶菌素9(PCSK9)是一种参与平衡胆固醇的蛋白酶。在结合到复杂的低密度脂蛋白(LDL)受体,PCSK9诱导其胞内降解,从而降低血清中LDL清除。PCSK9主要由肝脏分泌,其它脏器也有少许分泌,除了众所周知的关于肝LDL受体介导途径活性,PCSK9基因被认为可能潜在地干扰动脉粥样硬化血管炎症。血管平滑肌细胞已被证实能够产生比炎症微环境下的血管内皮细胞更多的PCSK9。在血管平滑肌细胞中,低剪切应力区域增加PCSK9的表达,而高剪切应力区域表达却逐渐减少。此外,PCSK9和活性氧簇之间串扰也已经被发现,氧化的低密度脂蛋白能呈剂量依赖性地影响IL-1α,IL-6和TNF-α的分泌,从而上调pcks9表达。在验证缺失功能突变的基因和没有检测到循环蛋白水平后,PCSK9作为降胆固醇治疗的有效靶点引起了人们极大的兴趣。不同的策略已经实施阻断细胞内和循环PCSK9基因的影响。尤其是,单克隆抗体代表着最有希望的方法,包括两个alirocumab 和evolocumab ,已经被批准用于家族性高胆固醇血症患者的临床应用且有较好的治疗效果。在未来,PCSK9抑制剂多效性的影响的知识改进也许会开发独立于降胆固醇活性的心血管治疗潜能。
关键词: 前蛋白转化酶枯草溶菌素9,alirocumab,evolocumab,炎症,动脉粥样硬化,胆固醇
Current Medicinal Chemistry
Title:Treatment with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors to Reduce Cardiovascular Inflammation and Outcomes
Volume: 24 Issue: 14
关键词: 前蛋白转化酶枯草溶菌素9,alirocumab,evolocumab,炎症,动脉粥样硬化,胆固醇
摘要: Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is a serine protease involved in cholesterol homeostasis. After binding to the complex low-density lipoprotein (LDL)-receptor, PCSK9 induces its intracellular degradation, thus reducing serum LDL clearance. PCSK9 is mainly secreted by the liver, but it is also expressed to a lesser extent in other organs. Apart from the well-known activity concerning hepatic LDL receptor-mediated pathway, PCSK9 has been supposed to potentially interfere with vascular inflammation in atherogenesis. Vascular smooth muscle cells have been demonstrated to produce higher amounts of PCSK9 as compared to endothelial cells especially in an inflammatory microenvironment. Low shear stress regions increase PCSK9 expression within SMCs, while higher shear stress gradually reduced PCSK9 expression. Moreover, a crosstalk between PCSK9 and reactive oxygen species has been also described. Oxidized LDL was shown to up regulate the expression of PCKS9 by influencing dose-dependently the secretion of interleukin (IL)-1α, IL-6, and tumor necrosis factor-α. After the identification of gene loss-of-function mutations and no detectable circulating protein levels, PCSK9 has attracted a great interest as an effective target for cholesterol-lowering therapies. Different strategies have been implemented to block the effects of both intracellular and circulating PCSK9. In particular, monoclonal antibodies represent the most promising approach and two of these, alirocumab and evolocumab, have been approved for clinical use in patients affected by familial hypercholesterolemia with encouraging results. In the next future, the improvement of the knowledge of the “pleiotropic” effects of PCSK9 inhibitors might unveil therapeutic potential on cardiovascular outcome independently on the cholesterol lowering activity.
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Cite this article as:
Treatment with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors to Reduce Cardiovascular Inflammation and Outcomes, Current Medicinal Chemistry 2017; 24 (14) . https://dx.doi.org/10.2174/0929867324666170303123734
DOI https://dx.doi.org/10.2174/0929867324666170303123734 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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