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.
Highlights
LDL cholesterol (LDL-C) contributes to coronary heart disease
We demonstrate that circulating cholesterol and atherosclerotic lesions are minimally modified in pcsk9Ϫ/Ϫ mice on either an ldlrϪ/Ϫ or an apoeϪ/Ϫ background, strongly suggesting requirement of both proteins for robust atheroprotection mediated by Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition
We demonstrate the ability of anti-PCSK9 monoclonal antibody to robustly reduce atherosclerosis in a mouse model with a functional ApoE-LDL receptor (LDLR) pathway, but with no effect when ApoE is absent
Summary
LDL cholesterol (LDL-C) contributes to coronary heart disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases LDL-C by inhibiting LDL-C clearance. 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. 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.—Ason, B., J. High levels of circulating LDL cholesterol (LDL-C) play a key role in the initiation and development of atherosclerosis This contributes to the development of CVD and places patients at increased risk of experiencing an adverse cardiovascular event [1, 2].
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