An Update on the Role of PCSK9 in Atherosclerosis

Abstract

Atherosclerosis is initiated by functional changes in the endothelium accompanied by accumulation, oxidation, and glycation of LDL-cholesterol in the inner layer of the arterial wall and continues with the expression of adhesion molecules and release of chemoattractants. PCSK9 is a proprotein convertase that increases circulating LDL levels by directing hepatic LDL receptors into lysosomes for degradation. The effects of PCSK9 on hepatic LDL receptors and contribution to atherosclerosis via the induction of hyperlipidemia are well defined. Monoclonal PCSK9 antibodies that block the effects of PCSK9 on LDL receptors demonstrated beneficial results in cardiovascular outcome trials. In recent years, extrahepatic functions of PCSK9, particularly its direct effects on atherosclerotic plaques have received increasing attention. Experimental trials have revealed that PCSK9 plays a significant role in every step of atherosclerotic plaque formation. It contributes to foam cell formation by increasing the uptake of LDL by macrophages via scavenger receptors and inhibiting cholesterol efflux from macrophages. It induces the expression of inflammatory cytokines, adhesion molecules, and chemoattractants, thereby increasing monocyte recruitment, inflammatory cell adhesion, and inflammation at the atherosclerotic vascular wall. Moreover, low shear stress is associated with increased PCSK9 expression. PCSK9 may induce endothelial cell apoptosis and autophagy and stimulate the differentiation of smooth muscle cells from the contractile phenotype to synthetic phenotype. Increasing evidence indicates that PCSK9 is a molecular target in the development of novel approaches toward the prevention and treatment of atherosclerosis. This review focuses on the molecular roles of PCSK9 in atherosclerotic plaque formation.

Keywords: Atherosclerosis; Form cell; Inflammation; PCSK9; Vascular wall.

Fig. 1.

Foam cell formation. LDL enters into the intimal layer of the artery and oxidized by reactive oxygen species. Macrophages engulf oxidized LDL by scavenger receptors such as CD36 and LOX-1 ABCA1 receptor maintains cholesterol efflux from macrophage. PCSK9 contributes to the formation of foam cells by inducing scavenger receptors, inhibiting the ABCA1 receptor, and directing ApoEr2 to the lysosomes for degradation.

Fig. 2.

Inflammation PCSK9 induces the expression of endothelial adhesion molecules. NF-KB nuclear translocation is induced by PCSK9, leading to an increase in mRNA levels and secretion of inflammatory cytokines.

Fig. 3.

Apoptosis PCSK9 induces apoptosis of HUVECs by inducing Bax and inhibiting Bcl2.