Proprotein convertase subtilisin/kexin type 9 potentially influences cholesterol uptake in macrophages and reverse cholesterol transport

Abstract

Edited by Laszlo NagyKeywords: PCSK9 Reverse cholesterol transport Low-density lipoprotein receptor Atherosclerosis a b s t r a c t Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of low-density lipoprotein receptor (LDLRs) molecules expressed on the cell surface. Gene inactivation of PCSK9 reduces the areas of atherosclerotic lesions in mice, and the effect is mainly dependent on LDLRs. Furthermore, a positive relationship between PCSK9 and cholesterol accumulation in the wall of the aorta has been established. However, the mechanism remains unknown. As PCSK9 is mainly expressed in atherosclerotic plaque and in the liver, we hypothesize that PCSK9 might increase oxidized LDL uptake and impair macrophage-mediated reverse cholesterol transport, contributing to the development of atherosclerosis.

PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE

“…Previously, Ferri et al ( 77 ) reported that PCSK9 is expressed in human vessel walls and produced locally by vessel smooth muscle cells causing a local effect, and it was suggested that PCSK9 could enter the subendothelial space from the circulation either by itself or in association with LDL. In addition, it has been hypothesized that PCSK9 could impact the expression of LDLR on lesion monocytes and macrophages modulating foam cell formation and/or promoting apoptosis ( 78 ). Although our analysis was quite limited, we conclude that PCSK9-mediated local effects at the lesion, refl ected by lesion area and macrophage number, is not signifi cant in the models utilized here.…”

Effects of lipoprotein apheresis on PCSK9 levels

“…It is possible that in apheresis patients the acute elimination of the PCSK9 protein may also improve the effectiveness of lipid-lowering drugs. It has been suggested that PCSK9 may be directly involved with the formation of atherosclerotic lesions by increasing oxidized LDL uptake and impairing macrophage-mediated reverse cholesterol transport [28]. Additionally, hypertensive patients with elevated serum PCSK9 levels were associated with increased carotid intima media thickness [29].…”

Hepatitis C virus and proprotein convertase subtilisin/kexin type 9: a detrimental interaction to increase viral infectivity and disrupt lipid metabolism

“…Finally, Shen et al . suggested that PCSK9 contributed to subendothelial oxidized LDL accumulation, which in turn might reduce SR‐B1 expression 22.…”