Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels
Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels
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DOI：
10.1016/j.atherosclerosis.2011.11.026
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发表时间：
2012-02-01
期刊：
影响因子：
5.3
通讯作者：
Catapano, Alberico Luigi
中科院分区：
文献类型：
--
作者：
Ferri, Nicola;Tibolla, Gianpaolo;Catapano, Alberico Luigi
目的：前蛋白转化酶枯草杆菌蛋白酶kexin 9型（PCSK 9）是肝脏低密度脂蛋白（LDL）-胆固醇水平的重要调节剂。虽然PCSK 9主要是肝起源，肝外组织显着贡献PCSK 9生产和潜在的，本地调节LDL receptor expression.Methods和结果：在本研究中，我们表明，在血管细胞中，PCSK 9在平滑肌细胞（SMC），但不是在内皮细胞，巨噬细胞和单核细胞中表达。PCSK 9在人动脉粥样硬化斑块中也可检测到。SMC的条件培养基显著降低人巨噬细胞和巨噬细胞系J774中的LDLR表达。共培养实验也证明了SMC对J774中LDLR表达的影响。SMC释放的PCSK 9直接调节巨噬细胞中LDLR的表达，这一点通过逆转录病毒过表达或用小干扰RNA敲减PCSK 9以及使用重组PCSK 9得到证明。此外，LDLR下调不需要PCSK 9的蛋白水解活性，因为含有无催化活性的PCSK 9或PCSK 9 WT的培养基对J774中的LDLR具有相似的影响。最后，SMCs的条件培养液影响巨噬细胞对β-VLDL胆固醇的摄取，PCSK 9的表达降低了巨噬细胞对LDLR和LDL的摄取。结论：SMCs分泌的PCSK 9具有功能活性，能够降低巨噬细胞的LDLR表达。一个可能的直接作用，这种蛋白质在泡沫细胞的形成和动脉粥样硬化的建议。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
Objective: Proprotein convertase subtilisin kexin type 9 (PCSK9) is an important regulator of hepatic low-density lipoprotein (LDL)-cholesterol levels. Although PCSK9 is mainly of hepatic origin, extra-hepatic tissues significantly contribute to PCSK9 production and, potentially, local regulation of LDL receptor expression.Methods and results: In the present study we show that, among vascular cells, PCSK9 is expressed in smooth muscle cells (SMCs) but not in endothelial cells, macrophages and monocytes. PCSK9 was also detectable in human atherosclerotic plaques. Conditioned media from SMCs significantly reduced LDLR expression in human macrophage and in the macrophage cell line J774. Co-culture experiments also demonstrated the influence of SMCs on LDLR expression in J774. PCSK9 released from SMCs directly regulated LDLR expression in macrophages as demonstrated by retroviral overexpression or knockdown of PCSK9 with small interfering RNA and by using recombinant PCSK9. Moreover, the proteolytic activity of PCSK9 was not required for LDLR downregulation since cultured media containing either the catalytic inactive PCSK9 or PCSK9 WT had a similar effect on LDLR in J774. Finally, conditioned media from SMCs affected beta-VLDL cholesterol uptake and PCSK9 expression reduced both LDLR and LDL uptake in J774.Conclusions: Taken together our data indicate that PCSK9 secreted by human SMCs is functionally active and capable of reducing LDLR expression in macrophages. A possible direct role for this protein in foam cell formation and atherogenesis is suggested. (C) 2011 Elsevier Ireland Ltd. All rights reserved.