PCSK9 inhibition fails to alter hepatic LDLR,circulating cholesterol,and atherosclerosis in the absence of ApoE |
| |
Authors: | Brandon Ason José W A van der Hoorn Joyce Chan Edward Lee Elsbet J Pieterman Kathy Khanh Nguyen Mei Di Susan Shetterly Jie Tang Wen-Chen Yeh Margrit Schwarz J Wouter Jukema Rob Scott Scott M Wasserman Hans M G Princen Simon Jackson |
| |
Institution: | *Metabolic Disorders Amgen, Inc., South San Francisco, CA;§Protein Technologies, Amgen, Inc., South San Francisco, CA;†TNO-Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands;**Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands;††Cardiovascular, Amgen Inc., Thousand Oaks, CA |
| |
Abstract: | 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. |
| |
Keywords: | apolipoprotein E anti-proprotein convertase subtilisin/kexin type 9 antibody low density lipoprotein receptor proprotein convertase subtilisin/kexin type 9 |
本文献已被 ScienceDirect 等数据库收录! |
|