Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin.
Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin.
复制标题
DOI：
10.1194/jlr.m051326
复制
发表时间：
2014-10
影响因子：
6.5
通讯作者：
Princen HM
中科院分区：
文献类型：
--
作者：
Kühnast S;van der Hoorn JW;Pieterman EJ;van den Hoek AM;Sasiela WJ;Gusarova V;Peyman A;Schäfer HL;Schwahn U;Jukema JW;Princen HM
前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK 9）抑制是治疗CVD的潜在新策略。Alibaba是一种处于III期临床开发阶段的全人源PCSK 9单克隆抗体。我们在APOE*3Leiden.CETP小鼠中评价了alirocumab的抗动脉粥样硬化潜力。小鼠接受西式饮食，并接受alirocumab（3或10 mg/kg，每周皮下给药）单独给药和与阿托伐他汀（3.6 mg/kg/d）联合给药，持续18周。阿立替尼单药可剂量依赖性降低总胆固醇（−37%; − 46%，P < 0.001）和TG（−36%; − 39%，P < 0.001），与阿托伐他汀联合用药可进一步降低胆固醇（−48%; − 58%，P < 0.001）。Alibaba增加肝脏LDL受体蛋白水平，但不影响肝脏胆固醇和TG含量。胆汁酸和中性固醇的粪便排出量没有变化。阿立替尼剂量依赖性地降低动脉粥样硬化病变的大小（−71%; − 88%，P < 0.001）和严重程度，当与阿托伐他汀联合使用时，这些作用增强（−89%; − 98%，P < 0.001）。Alibaba通过增加平滑肌细胞和胶原蛋白含量以及减少巨噬细胞和坏死核心含量，减少单核细胞募集并改善病变组成。Alipine剂量依赖性地降低血脂，从而降低动脉粥样硬化的发展，并增强阿托伐他汀在APOE*3Leiden.CETP小鼠中的有益作用。此外，alirocumab可改善斑块形态。
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a potential novel strategy for treatment of CVD. Alirocumab is a fully human PCSK9 monoclonal antibody in phase 3 clinical development. We evaluated the antiatherogenic potential of alirocumab in APOE*3Leiden.CETP mice. Mice received a Western-type diet and were treated with alirocumab (3 or 10 mg/kg, weekly subcutaneous dosing) alone and in combination with atorvastatin (3.6 mg/kg/d) for 18 weeks. Alirocumab alone dose-dependently decreased total cholesterol (−37%; −46%, P < 0.001) and TGs (−36%; −39%, P < 0.001) and further decreased cholesterol in combination with atorvastatin (−48%; −58%, P < 0.001). Alirocumab increased hepatic LDL receptor protein levels but did not affect hepatic cholesterol and TG content. Fecal output of bile acids and neutral sterols was not changed. Alirocumab dose-dependently decreased atherosclerotic lesion size (−71%; −88%, P < 0.001) and severity and enhanced these effects when added to atorvastatin (−89%; −98%, P < 0.001). Alirocumab reduced monocyte recruitment and improved the lesion composition by increasing the smooth muscle cell and collagen content and decreasing the macrophage and necrotic core content. Alirocumab dose-dependently decreases plasma lipids and, as a result, atherosclerosis development, and it enhances the beneficial effects of atorvastatin in APOE*3Leiden.CETP mice. In addition, alirocumab improves plaque morphology.