Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain; Institute of Health Research INCLIVA, Av. Menéndez Pelayo 4, 46010 Valencia, Spain.
Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain.
Biomed Pharmacother. 2022 Jan;145:112460. doi: 10.1016/j.biopha.2021.112460. Epub 2021 Dec 2.
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 TNFα-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 CXCR1, 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 IFNγ 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 TNFα stimulation of HUAEC increased the expression of PCSK9, whereas endothelial PCSK9 silencing reduced TNFα-induced mononuclear cell adhesion mediated by Nox5 up-regulation and p38-MAPK/NFκB activation, concomitant with reduced SREBP2 expression. PCSK9 silencing also decreased endothelial CXCL1 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.
家族性高胆固醇血症（FH）与低度全身炎症有关，而全身炎症是动脉粥样硬化过早发生的关键驱动因素。我们研究了抑制前蛋白转化酶枯草溶菌素/克那霉 9（PCSK9）功能对 FH 患者炎症状态、内皮功能障碍和心血管结局的影响。14 例 FH 患者在接受 PCSK9 阻断单克隆抗体（alirocumab，150mg/皮下/14 天）治疗前和治疗 8 周后进行了评估。体内和体外分析显示，alirocumab 减弱了白细胞与 TNFα 刺激的人脐动脉内皮细胞（HUAEC）的附着，并抑制了血小板和大多数白细胞亚群的激活，这伴随着几种白细胞亚群上 CXCR1、CXCR6 和 CCR2 的表达减少。相比之下，alirocumab 治疗增强了 T 调节细胞的激活，同时也提高了抗炎性 IL-10 血浆水平并降低了循环促炎细胞因子水平。血浆 IFNγ 水平与总胆固醇和 LDL 胆固醇水平呈正相关，而循环 IL-10 水平与这些关键脂质参数呈负相关。体外分析显示，TNFα 刺激 HUAEC 增加了 PCSK9 的表达，而内皮 PCSK9 沉默减少了由 Nox5 上调和 p38-MAPK/NFκB 激活介导的 TNFα 诱导的单核细胞粘附，同时伴随着 SREBP2 表达减少。PCSK9 沉默也降低了内皮 CXCL1 和 CXCL16 的表达和趋化因子生成。总之，PCSK9 抑制通过限制白细胞-内皮相互作用来损害全身炎症和内皮功能障碍。PCSK9 阻断可能成为控制 FH 相关炎症状态的新治疗方法，防止这种代谢性心血管疾病中进一步的心血管事件发生。
