Title
PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE
Author
Ason, B.
van der Hoorn, J.W.A.
Chan, J.
Lee, E.
Pieterman, E.J.
Nguyen, K.K.
Di, M.
Shetterly, S.
Tang, J.
Yeh, W.C.
Schwarz, M.
Jukema, J.W.
Scott, R.
Wasserman, S.M.
Princen, H.M.G.
Jackson, S.
Publication year
2014
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.
Subject
ELSS - Earth, Life and Social Sciences
Life
Healthy Living
Biomedical Innovation
Anti-proprotein convertase subtilisin/kexin type 9 antibody
Apolipoprotein E
Low density lipoprotein receptor
Proprotein convertase subtilisin/kexin type 9
MHR - Metabolic Health Research
To reference this document use:
http://resolver.tudelft.nl/uuid:72910b10-4f69-4d5e-878d-cbd0417f30f1
DOI
https://doi.org/10.1194/jlr.m053207
TNO identifier
520224
ISSN
0022-2275
Source
Journal of Lipid Research, 55 (55), 2370-2379
Document type
article