Research progress on alternative non-classical mechanisms of PCSK9 in atherosclerosis in patients with and without diabetes

Abstract

The proprotein convertase subtilisin/kexin type 9 (PCSK9) acts via a canonical pathway to regulate circulating lowdensity lipoprotein-cholesterol (LDL-C) via degradation of the LDL receptor (LDLR) on the liver cell surface. Published research has shown that PCSK9 is involved in atherosclerosis via a variety of non-classical mechanisms that involve lysosomal, inflammatory, apoptotic, mitochondrial, and immune pathways. In this review paper, we summarized these additional mechanisms and described how anti-PCSK9 therapy exerts effects through these mechanisms. These additional pathways further illustrate the regulatory role of PCSK9 in atherosclerosis and offer an in-depth interpretation of how the PCSK9 inhibitor exerts effects on the treatment of atherosclerosis.

Depression and cardiovascular risk—association among Beck Depression Inventory, PCSK9 levels and insulin resistance

“…A genetic reduction of PCSK9 levels by 50% is associated with a similar percent reduction of coronary heart disease (CHD) risk [ 59 ] and a genetic large-scale study on 337,536 individuals of British ancestry reported that the rs11591147 PCSK9 mutation had a protective effect not only on hyperlipidemia, but also on the risk of CHD (− 27%) and ischemic stroke (− 39%) [ 60 ]. A further hypothesis linking PCSK9 to atherosclerosis is the direct role that this protein can play on atherogenesis (reviewed in [ 61 ]). Indeed, PCSK9, expressed in vascular smooth muscle cells, human atherosclerotic plaques and epicardial adipose tissue [ 62 ], reduces macrophage cholesterol efflux capacity, raises the migratory ability of monocytes and the expression of scavenger receptors, thus enhancing ox-LDL uptake in monocytes and macrophages.…”

Association of circulating proprotein convertase subtilisin/kexin type 9 levels and the risk of incident type 2 diabetes in subjects with prediabetes: a population-based cohort study

“…The best-known function of PCSK9 is posttranslational regulation of LDLR on hepatocytes, which is the major route for LDL-C clearance from the circulation. In addition to from the canonical pathway, PCSK9 regulates lipid metabolism by intracellular endogenous PCSK9-induced LDLR degradation, VLDLR degradation, regulation of apolipoprotein B secretion, and lipoprotein(a) metabolism [ 5 , 22 ]. PCSK9 is also associated with macrophage cholesterol efflux, apoptosis of endothelial cells, mitochondrial dysfunction, and inflammation [ 5 ], which contribute to metabolic disturbance.…”

“…In addition to from the canonical pathway, PCSK9 regulates lipid metabolism by intracellular endogenous PCSK9-induced LDLR degradation, VLDLR degradation, regulation of apolipoprotein B secretion, and lipoprotein(a) metabolism [ 5 , 22 ]. PCSK9 is also associated with macrophage cholesterol efflux, apoptosis of endothelial cells, mitochondrial dysfunction, and inflammation [ 5 ], which contribute to metabolic disturbance. Furthermore, we found that PCSK9 was positively associated with ALT, AST, and GGT [ 23 ], liver function indices that are known as sensitive indicators of liver dysfunction and hepatic insulin resistance in diabetes [ 24 , 25 ].…”

“…The finding that PCSK9 acts as a regulator pathway for hepatic low-density lipoprotein receptor (LDLR) degradation through an endosomal/lysosomal pathway sheds light on newly uncovered issues regarding LDL cholesterol (LDL-C) homeostasis [ 4 ]. Apart from this classical pathway, recent studies have described other roles played by PCSK9 in atherosclerosis via a variety of nonclassical mechanisms that involve inflammatory, apoptotic, and immune pathways [ 5 ].…”

Depression and Cardiovascular Risk - Association Among Beck Depression Inventory, PCSK9 Levels and Insulin Resistance

“…A genetic reduction of PCSK9 levels by 50% is associated with a similar percent reduction of coronary heart disease (CHD) risk [59] and a genetic large-scale study on 337,536 individuals of British ancestry reported that the rs11591147 PCSK9 mutation had a protective effect not only on hyperlipidemia, but also on the risk of CHD (-27%) and ischemic stroke (-39%) [60]. A further hypothesis linking PCSK9 to atherosclerosis is the direct role that this protein can play on atherogenesis (reviewed in [61]). Indeed, PCSK9, expressed in vascular smooth muscle cells, human atherosclerotic plaques and epicardial adipose tissue [62], reduces macrophage cholesterol e ux capacity, raises the migratory ability of monocytes and the expression of scavenger receptors, thus enhancing ox-LDL uptake in monocytes and macrophages.…”