PCSK9 monoclonal antibodies reverse the pro-inflammatory profile of monocytes in familial hypercholesterolaemia
PCSK9 monoclonal antibodies reverse the pro-inflammatory profile of monocytes in familial hypercholesterolaemia
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DOI：
10.1093/eurheartj/ehx002
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发表时间：
2017-05-21
影响因子：
39.3
通讯作者：
Stroes, Erik S. G.
中科院分区：
文献类型：
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作者：
Moens, Sophie J. Bernelot;Neele, Annette E.;Stroes, Erik S. G.
目的单核细胞向动脉壁的迁移有助于动脉炎症和动脉粥样硬化的进展。由于低密度脂蛋白胆固醇(LDL-C)水平升高与血浆单核细胞活化有关，密集降低低密度脂蛋白胆固醇(LDL-C)可能逆转这些促炎变化。方法应用选择性降低低密度脂蛋白胆固醇(L DL-C)的原蛋白转换酶-枯草杆菌毒素/可信9型单抗研究他汀类肌肉症状导致的家族性高胆固醇血症(FH)患者单核细胞表型和功能的变化。方法与结果采用流式细胞术和跨内皮细胞迁移试验检测了22例FH患者(n=22：LDL6.8+/-1.9 mmol/L)和18例健康对照(n=18，LDL2.9+/-0.8 mmol/L)单核细胞表型和功能。FH患者单核细胞趋化因子受体(CCR)2的表达约为对照组的三倍。C-C趋化因子受体2型表达与低密度脂蛋白水平呈显著正相关(r=0.709)，与细胞内脂质积聚呈正相关。FH患者的单核细胞体外迁移能力也增强。经PCSK9单抗治疗24周后(n=17)，血浆低密度脂蛋白-C下降了49%，这与细胞内脂质堆积减少和CCR2表达减少相一致。PCSK9单抗治疗后单核细胞迁移能力增强的逆转证实了功能相关性。结论FH患者单核细胞具有促炎表型，这种表型可被PCSK9单抗治疗后的低密度脂蛋白降低所抑制。低密度脂蛋白的降低与细胞内脂质堆积的减少是平行的，这表明低密度脂蛋白的降低本身与对循环单核细胞的抗炎作用有关。
Aims Migration of monocytes into the arterial wall contributes to arterial inflammation and atherosclerosis progression. Since elevated low-density lipoprotein cholesterol (LDL-C) levels have been associated with activation of plasma monocytes, intensive LDL-C lowering may reverse these pro-inflammatory changes. Using proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) which selectively reduce LDL-C, we studied the impact of LDL-C lowering on monocyte phenotype and function in patients with familial hypercholesterolaemia (FH) not using statins due to statin-associated muscle symptoms.Methods and results We assessed monocyte phenotype and function using flow cytometry and a trans-endothelial migration assay in FH patients (n = 22: LDL 6.8 +/- 1.9 mmol/L) and healthy controls (n = 18, LDL 2.9 +/- 0.8 mmol/L). Monocyte chemokine receptor (CCR) 2 expression was approximaterly three-fold higher in FH patients compared with controls. C-C chemokine receptor type 2 (CCR2) expression correlated significantly with plasma LDL-C levels (r = 0.709) and was positively associated with intracellular lipid accumulation. Monocytes from FH patients also displayed enhanced migratory capacity ex vivo. After 24 weeks of PCSK9 mAb treatment (n = 17), plasma LDL-C was reduced by 49%, which coincided with reduced intracellular lipid accumulation and reduced CCR2 expression. Functional relevance was substantiated by the reversal of enhanced migratory capacity of monocytes following PCSK9 mAb therapy.Conclusions Monocytes of FH patients have a pro-inflammatory phenotype, which is dampened by LDL-C lowering by PCSK9 mAb therapy. LDL-C lowering was paralleled by reduced intracellular lipid accumulation, suggesting that LDL-C lowering itself is associated with anti-inflammatory effects on circulating monocytes.