Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition A New Therapeutic Mechanism for Reducing Cardiovascular Disease Risk
Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition A New Therapeutic Mechanism for Reducing Cardiovascular Disease Risk
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DOI：
10.1161/circulationaha.115.016080
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发表时间：
2015-10-27
期刊：
影响因子：
37.8
通讯作者：
Krauss, Ronald M.
中科院分区：
文献类型：
--
作者：
Bergeron, Nathalie;Phan, Binh An P.;Krauss, Ronald M.
前蛋白转化酶枯草杆菌蛋白酶9（PCSK 9）在胆固醇稳态调节中起重要作用。通过与肝脏低密度脂蛋白（LDL）受体结合并促进其溶酶体降解，PCSK 9减少LDL摄取，导致LDL胆固醇浓度升高。与高LDL胆固醇和早发心血管疾病相关的PCSK 9功能获得性突变与常染色体显性遗传家族性高胆固醇血症的病理生理学有因果关系。相比之下，PCSK 9中更常见的功能丧失突变与LDL胆固醇和心血管疾病风险降低相关。因此，抑制PCSK 9功能的治疗方法的开发引起了临床医生和制药行业对高胆固醇血症及其相关心血管疾病风险管理的极大关注。本文综述了PCSK 9对肝脏和肠道脂质代谢的影响，以及最近对PCSK 9在肝外组织中功能的研究。还描述了防止PCSK 9与肝脏LDL受体相互作用（单克隆抗体、模拟肽）、抑制内质网中PCSK 9合成（反义寡核苷酸、SiRNA）以及干扰PCSK 9功能（小分子）的治疗方法。最后，临床试验测试的安全性和有效性的单克隆抗体PCSK 9进行审查。这些研究表明，LDL胆固醇（44%-65%）、载脂蛋白B（48%-59%）和脂蛋白（a）（27%-50%）呈剂量依赖性降低，在各种高危患者类别（包括他汀类药物不耐受患者）中无重大不良反应。其中2项试验的初步报告表明，预期心血管事件会减少。因此，抑制PCSK 9作为降低心血管疾病风险的治疗选择具有相当大的前景。
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the regulation of cholesterol homeostasis. By binding to hepatic low/density lipoprotein (LDL) receptors and promoting their lysosomal degradation, PCSK9 reduces LDL uptake, leading to an increase in LDL cholesterol concentrations. Gain-of-function mutations in PCSK9 associated with high LDL cholesterol and premature cardiovascular disease have been causally implicated in the pathophysiology of autosomal-dominant familial hypercholesterolemia. In contrast, the more commonly expressed loss-of-function mutations in PCSK9 are associated with reduced LDL cholesterol and cardiovascular disease risk. The development of therapeutic approaches that inhibit PCSK9 function has therefore attracted considerable attention from clinicians and the pharmaceutical industry for the management of hypercholesterolemia and its associated cardiovascular disease risk. This review summarizes the effects of PCSK9 on hepatic and intestinal lipid metabolism and the more recently explored functions of PCSK9 in extrahepatic tissues. Therapeutic approaches that prevent interaction of PCSK9 with hepatic LDL receptors (monoclonal antibodies, mimetic peptides), inhibit PCSK9 synthesis in the endoplasmic reticulum (antisense oligonucleotides, siRNAs), and interfere with PCSK9 function (small molecules) are also described. Finally, clinical trials testing the safety and efficacy of monoclonal antibodies to PCSK9 are reviewed. These have shown dose-dependent decreases in LDL cholesterol (44%-65%), apolipoprotein B (48%-59%), and lipoprotein(a) (27%-50%) without major adverse effects in various high-risk patient categories, including those with statin intolerance. Initial reports from 2 of these trials have indicated the expected reduction in cardiovascular events. Hence, inhibition of PCSK9 holds considerable promise as a therapeutic option for decreasing cardiovascular disease risk.