title: Treatment with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors to Reduce Cardiovascular Inflammation and Outcomes.
abstract: Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is a serine protease involved in cholesterol homeostasis. After binding to the complex low-density lipoprotein (LDL)-receptor, PCSK9 induces its intracellular degradation, thus reducing serum LDL clearance. PCSK9 is mainly secreted by the liver, but it is also expressed to a lesser extent in other organs. Apart from the well-known activity concerning hepatic LDL receptor-mediated pathway, PCSK9 has been supposed to potentially interfere with vascular inflammation in atherogenesis. Vascular smooth muscle cells have been demonstrated to produce higher amounts of PCSK9 as compared to endothelial cells especially in an inflammatory microenvironment. Low shear stress regions increase PCSK9 expression within SMCs, while higher shear stress gradually reduced PCSK9 expression. Moreover, a crosstalk between PCSK9 and reactive oxygen species has been also described. Oxidized LDL was shown to up regulate the expression of PCKS9 by influencing dose-dependently the secretion of interleukin (IL)-1α, IL-6, and tumor necrosis factor-α. After the identification of gene loss-of-function mutations and no detectable circulating protein levels, PCSK9 has attracted a great interest as an effective target for cholesterol-lowering therapies. Different strategies have been implemented to block the effects of both intracellular and circulating PCSK9. In particular, monoclonal antibodies represent the most promising approach and two of these, alirocumab and evolocumab, have been approved for clinical use in patients affected by familial hypercholesterolemia with encouraging results. In the next future, the improvement of the knowledge of the "pleiotropic" effects of PCSK9 inhibitors might unveil therapeutic potential on cardiovascular outcome independently on the cholesterol lowering activity.
authors.affiliation: First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa. Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Liberale
authors.affiliation: First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa. Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Montecucco
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren. Switzerland.
authors.forename: Giovanni G
authors.initials: GG
authors.lastname: Camici
authors.affiliation: First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa. Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Dallegri
authors.affiliation: First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa. Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Vecchie
authors.affiliation: First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa. Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Carbone
authors.affiliation: First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa. Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Bonaventura
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D000091362:PCSK9 Inhibitors; D000071449:Proprotein Convertase 9 / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000091362:PCSK9 Inhibitors; D015842:Serine Proteinase Inhibitors; D000071449:Proprotein Convertase 9
keywords: PCSK9; alirocumab; atherosclerosis; cholesterol; evolocumab; inflammation