title: PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE.
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.
authors.affiliation: Metabolic Disorders Amgen, Inc., South San Francisco, CA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Ason
authors.affiliation: TNO-Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands.
authors.forename: José W A
authors.initials: JW
authors.lastname: van der Hoorn
authors.affiliation: Metabolic Disorders Amgen, Inc., South San Francisco, CA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Chan
authors.affiliation: Metabolic Disorders Amgen, Inc., South San Francisco, CA.
authors.forename: Edward
authors.initials: E
authors.lastname: Lee
authors.affiliation: TNO-Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands.
authors.forename: Elsbet J
authors.initials: EJ
authors.lastname: Pieterman
authors.affiliation: Metabolic Disorders Amgen, Inc., South San Francisco, CA.
authors.forename: Kathy Khanh
authors.initials: KK
authors.lastname: Nguyen
authors.affiliation: Metabolic Disorders Amgen, Inc., South San Francisco, CA.
authors.forename: Mei
authors.initials: M
authors.lastname: Di
authors.affiliation: Metabolic Disorders Amgen, Inc., South San Francisco, CA.
authors.forename: Susan
authors.initials: S
authors.lastname: Shetterly
authors.affiliation: Protein Technologies, Amgen, Inc., South San Francisco, CA.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.affiliation: Metabolic Disorders Amgen, Inc., South San Francisco, CA.
authors.forename: Wen-Chen
authors.initials: WC
authors.lastname: Yeh
authors.affiliation: Metabolic Disorders Amgen, Inc., South San Francisco, CA.
authors.forename: Margrit
authors.initials: M
authors.lastname: Schwarz
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.affiliation: Cardiovascular, Amgen Inc., Thousand Oaks, CA.
authors.forename: Rob
authors.initials: R
authors.lastname: Scott
authors.affiliation: Cardiovascular, Amgen Inc., Thousand Oaks, CA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wasserman
authors.affiliation: TNO-Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands.
authors.forename: Hans M G
authors.initials: HM
authors.lastname: Princen
authors.affiliation: Metabolic Disorders Amgen, Inc., South San Francisco, CA.
authors.forename: Simon
authors.initials: S
authors.lastname: Jackson
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood*; D053480:Cholesterol Ester Transfer Proteins / Q000378:metabolism; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000906:Antibodies; D001057:Apolipoproteins E; D053480:Cholesterol Ester Transfer Proteins; D011973:Receptors, LDL; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: anti-proprotein convertase subtilisin/kexin type 9 antibody; apolipoprotein E; low density lipoprotein receptor; proprotein convertase subtilisin/kexin type 9