PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE
PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE
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DOI：
10.1194/jlr.m053207
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发表时间：
2014-11-01
影响因子：
6.5
通讯作者：
Jackson, Simon
中科院分区：
文献类型：
--
作者：
Ason, Brandon;van der Hoorn, Jose W. A.;Jackson, Simon
低密度脂蛋白胆固醇（LDL-C）会导致冠心病。前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型 (PCSK9) 通过抑制 LDL-C 清除来增加 LDL-C。 PCSK9 功能丧失携带者的循环 LDL-C 降低 15-30%，并且发生心血管事件的风险显着降低 (47-88%)，这一事实凸显了 PCSK9 抑制剂的治疗潜力。在这里，我们利用 pcsk9(-/-) 小鼠和抗 PCSK9 抗体来研究 LDL 受体 (LDLR) 和 ApoE 在 PCSK9 介导的血浆胆固醇调节和动脉粥样硬化病变发展中的作用。我们发现，在 LDLR 或 ApoE 缺陷的背景下，pcsk9(-/-) 小鼠的循环胆固醇和动脉粥样硬化病变发生了最小程度的改变。急性施用抗 PCSK9 抗体不会降低 ApoE 缺陷背景中的循环胆固醇，但确实降低了 APOE*3Leiden.胆固醇酯转移蛋白 (CETP) 小鼠的循环胆固醇 (-45%) 和 TG (-36%)，该小鼠含有小鼠 ApoE、人类突变体 APOE3*Leiden 和功能性 LDLR。 APOE*3Leiden 中的长期抗 PCSK9 抗体治疗。 CETP小鼠导致动脉粥样硬化病变面积显着减少（-91%）并降低病变复杂性。综上所述，这些结果表明 LDLR 和 ApoE 都是 PCSK9 抑制剂介导的动脉粥样硬化减少所必需的，因为两者都是增加肝脏 LDLR 表达所必需的。
LDL cholesterol (LDL-C) contributes to coronary heart disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases LDL-C by inhibiting LDL-C clearance. The therapeutic potential for PCSK9 inhibitors is highlighted by the fact that PCSK9 loss-of-function carriers exhibit 15-30% lower circulating LDL-C and a disproportionately lower risk (47-88%) of experiencing a cardiovascular event. Here, we utilized pcsk9(-/-) mice and an anti-PCSK9 antibody to study the role of the LDL receptor (LDLR) and ApoE in PCSK9-mediated regulation of plasma cholesterol and atherosclerotic lesion development. We found that circulating cholesterol and atherosclerotic lesions were minimally modified in pcsk9(-/-) mice on either an LDLR-or ApoE-deficient background. Acute administration of an anti-PCSK9 antibody did not reduce circulating cholesterol in an ApoE-deficient background, but did reduce circulating cholesterol (-45%) and TGs (-36%) in APOE*3Leiden.cholesteryl ester transfer protein (CETP) mice, which contain mouse ApoE, human mutant APOE3*Leiden, and a functional LDLR. Chronic anti-PCSK9 antibody treatment in APOE*3Leiden. CETP mice resulted in a significant reduction in atherosclerotic lesion area (-91%) and reduced lesion complexity. Taken together, these results indicate that both LDLR and ApoE are required for PCSK9 inhibitor-mediated reductions in atherosclerosis, as both are needed to increase hepatic LDLR expression.