PCSK9 deficiency reduces atherosclerosis, apolipoprotein B secretion, and endothelial dysfunction.
PCSK9 deficiency reduces atherosclerosis, apolipoprotein B secretion, and endothelial dysfunction.
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DOI：
10.1194/jlr.m078360
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发表时间：
2018-03
影响因子：
6.5
通讯作者：
Teng BB
中科院分区：
文献类型：
--
作者：
Sun H;Krauss RM;Chang JT;Teng BB
前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK 9）直接与细胞质apoB相互作用，并通过自噬体/溶酶体途径阻止其降解。该过程影响VLDL和LDL的产生并影响动脉粥样硬化形成。在这里，我们研究了PCSK 9调节自噬和影响动脉粥样硬化形成的分子机制。我们将Pcsk 9 −/−小鼠与易患动脉粥样硬化的Ldlr−/− Apobec 1 −/−（LDb）小鼠回交，以产生Ldlr−/− Apobec 1 −/− Pcsk 9 −/−（LTp）小鼠。PCSK 9的缺失导致肝脏apoB分泌减少，自噬通量增加，IDL和LDL颗粒的血浆水平降低。与LDb-LDL相比，LTp小鼠的LDL（LTp-LDL）致动脉粥样硬化性较低，并且含有较少的胆固醇酯和磷脂。此外，LTp-LDL诱导编码TLR 2、Lox-1、ICAM-1、CCL 2、CCL 7、IL-6、IL-1β、Beclin-1、p62和TRAF 6的基因的内皮表达降低。总的来说，这些作用与LTp小鼠中动脉粥样硬化发展显著减少（>4倍）相关。LDb小鼠中PCSK 9的缺失导致脂质和apoB水平降低、致动脉粥样硬化LDL减少和动脉粥样硬化显著减少。对动脉粥样硬化形成的影响可能部分通过修饰的LDL对内皮细胞受体和促炎分子和自噬分子的影响来介导。这些发现表明，由于与LDL受体活性增加无关的机制，PCSK 9抑制可能具有临床获益。
Proprotein convertase subtilisin/kexin type 9 (PCSK9) interacts directly with cytoplasmic apoB and prevents its degradation via the autophagosome/lysosome pathway. This process affects VLDL and LDL production and influences atherogenesis. Here, we investigated the molecular machinery by which PCSK9 modulates autophagy and affects atherogenesis. We backcrossed Pcsk9−/− mice with atherosclerosis-prone Ldlr−/−Apobec1−/− (LDb) mice to generate Ldlr−/−Apobec1−/−Pcsk9−/− (LTp) mice. Deletion of PCSK9 resulted in decreased hepatic apoB secretion, increased autophagic flux, and decreased plasma levels of IDL and LDL particles. The LDLs from LTp mice (LTp-LDLs) were less atherogenic and contained less cholesteryl ester and phospholipids than LDb-LDLs. Moreover LTp-LDLs induced lower endothelial expression of the genes encoding TLR2, Lox-1, ICAM-1, CCL2, CCL7, IL-6, IL-1β, Beclin-1, p62, and TRAF6. Collectively, these effects were associated with substantially less atherosclerosis development (>4-fold) in LTp mice. The absence of PCSK9 in LDb mice results in decreased lipid and apoB levels, fewer atherogenic LDLs, and marked reduction of atherosclerosis. The effect on atherogenesis may be mediated in part by the effects of modified LDLs on endothelial cell receptors and proinflammatory and autophagy molecules. These findings suggest that there may be clinical benefits of PCSK9 inhibition due to mechanisms unrelated to increased LDL receptor activity.