An Update on the Role of PCSK9 in Atherosclerosis

Abstract

The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Review 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.

Autocrine effects of PCSK9 on cardiomyocytes

“…The exact mechanisms of PCSK9 mediated impaired cardiomyocyte/myocardial function and in this context binding/interaction partner of PCSK9 in cardiomyocytes have to be identified. Here a modulation of autophagy of cardiomyocytes mediated by PCSK9 could play a role [9,37].…”

PCSK9 Functions in Atherosclerosis Are Not Limited to Plasmatic LDL-Cholesterol Regulation

“…PCSK9 modulates the expression of the apoptosis inducer Bax and the apoptosis inhibitor Bcl-2. The balance between these two proteins is key to prevent or trigger apoptosis ( 66 , 67 ). Lipid loaded endothelial cells show increased Bax protein levels and decreased Bcl-2 levels that lead to caspase 3 and caspase 9 activation inducing cell apoptosis ( 68 ).…”

PCSK9 and atherosclerosis: Looking beyond LDL regulation

“…The established evidence that PCSK9 degrades LDLR in the liver resulting in increased levels of LDL‐C 3 led to the rapid development of effective anti‐PCSK9 treatments (anti‐PCSK9 monoclonal antibody). Currently, two human monoclonal antibodies, evolocumab and alirocumab, are approved for use in patients at high‐risk of coronary artery disease 8,11,12 .…”

“…Atherosclerosis may be defined as an inflammatory pathological process of large arteries leading to coronary artery disease (CAD), ischaemic stroke and other cardiovascular diseases 1‐3 . Development and progression of the atherosclerotic plaque involve the interplay between circulating levels of low‐density lipoproteins (LDL), rich in cholesterol (LDL‐C) and the activation of various cellular processes including, among others, endothelial cell (EC) dysfunction/activation and apoptosis, smooth muscle cell (SMC) proliferation and migration into the intima, T‐cell and macrophage activation and foam cell formation (Figure 1).…”

“…The role of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) in this context has rapidly evolved from its discovery as a genetic determinant of some forms of familial hypercholesterolaemia to its use as the target of new lipid‐lowering drugs now tested or being tested in clinical trials 3,7,8 . PCSK9 is an enzyme able to regulate serum LDL‐C levels through the degradation of the LDL receptor (LDLR) 3 . Blocking PCSK9 with specific inhibitors thus causes a significant decrease of LDL‐C blood levels both in healthy volunteers and in individuals with hypercholesterolaemia, with and without statin co‐treatment 8‐12 …”