Beneficial effects of PCSK9 inhibition with alirocumab in familial hypercholesterolemia involve modulation of new immune players

Fecha de publicación: 01/01/2022 Fecha Ahead of Print: 01/12/2021

Grupos y Plataformas de I+D+i

• Grupo de Investigación en Inflamación

  

  Leading Researcher

  Maria Jesus Sanz Ferrando

• Grupo de Investigación en Receptores Nucleares en Patología Cardiometabólicas

  

  Established Researcher

  Laura Piqueras Ruiz

• Grupo de Investigación sobre Riesgo Cardiometabólico y Diabetes

  

  Leading Researcher

  Sergio Martinez Hervas

Abstract

Familial hypercholesterolemia (FH) is associated with low-grade systemic inflammation, a key driver of premature atherosclerosis. We investigated the effects of inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) function on inflammatory state, endothelial dysfunction and cardiovascular outcomes in patients with FH. Fourteen patients with FH were evaluated before and 8 weeks after administration of a PCSK9 blocking monoclonal antibody (alirocumab, 150 mg/subcutaneous/14 days). In vivo and ex vivo analysis revealed that alirocumab blunted the attachment of leukocytes to TNF alpha-stimulated human umbilical arterial endothelial cells (HUAEC) and suppressed the activation of platelets and most leukocyte subsets, which was accompanied by the diminished expression of CX(3)CR1, CXCR6 and CCR2 on several leukocyte subpopulations. By contrast, T-regulatory cell activation was enhanced by alirocumab treatment, which also elevated anti-inflammatory IL-10 plasma levels and lowered circulating pro-inflammatory cytokines. Plasma levels of IFN gamma positively correlated with levels of total and LDL-cholesterol, whereas circulating IL-10 levels negatively correlated with these key lipid parameters. In vitro analysis revealed that TNF alpha stimulation of HUAEC increased the expression of PCSK9, whereas endothelial PCSK9 silencing reduced TNF alpha-induced mononuclear cell adhesion mediated by NoxS upregulation and p38-MAPK/NF kappa B activation, concomitant with reduced SREBP2 expression. PCSK9 silencing also decreased endothelial CX(3)CL1 and CXCL16 expression and chemokine generation. In conclusion, PCSK9 inhibition impairs systemic inflammation and endothelial dysfunction by constraining leukocyte-endothelium interactions. PCSK9 blockade may constitute a new therapeutic approach to control the inflammatory state associated with FH, preventing further cardiovascular events in this cardiometabolic disorder.

Keywords

• Familial hypercholesterolemia; PCSK9; Alirocumab; Systemic inflammation; Endothelial dysfunction; Atherosclerosis