Local effects of human PCSK9 on the atherosclerotic lesion.
Local effects of human PCSK9 on the atherosclerotic lesion.
复制标题
DOI：
10.1002/path.4630
复制
发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Fazio S
中科院分区：
文献类型：
--
作者：
Giunzioni I;Tavori H;Covarrubias R;Major AS;Ding L;Zhang Y;DeVay RM;Hong L;Fan D;Predazzi IM;Rashid S;Linton MF;Fazio S
蛋白转化酶枯草素/可辛9型（PCSK9）通过降解肝脏LDL受体（LDLR），增加低密度脂蛋白（LDL）胆固醇水平，从而促进动脉粥样硬化。研究已经描述了PCSK9对动脉粥样硬化的全身作用，但PCSK9是否对斑块有局部和直接作用尚不清楚。为了研究人类PCSK9 （hPCSK9）对动脉粥样硬化病变组成的局部影响，不依赖于血清胆固醇水平的变化，我们利用hPCSK9转基因（hPCSK9tg）小鼠的骨髓移植到apoE - / -和LDLR - / -小鼠体内，产生巨噬细胞表达hPCSK9的嵌合小鼠，然后将它们置于高脂肪饮食中8周。我们进一步表征了hPCSK9表达对脾脏和小鼠腹膜巨噬细胞（MPM）炎症反应的影响。我们发现转基因小鼠的MPM同时表达小鼠(m) Pcsk9和hPCSK9，后者降低巨噬细胞LDLR和LRP1的表面水平。移植hPCSK9tg骨髓小鼠血清中检测到hPCSK9，但不影响脂质水平和动脉粥样硬化病变大小。然而，骨髓来源的PCSK9在apoE−/−受体小鼠的病变中逐渐积累，与对照组相比，Ly6Chi炎症单核细胞的浸润增加了32%。hPCSK9的表达也增加了apoE−/−小鼠脾脏中CD11b和Ly6Chi阳性细胞的数量。在体外，lps刺激的巨噬细胞中表达hPCSK9使促炎标志物Tnf和Il1b mRNA水平升高（分别为40%和45%），抑制抗炎标志物Il10和Arg1 mRNA水平（分别为30%和44%）。所有PCSK9效应都是LDLR依赖性的，因为在LDLR−/−受体小鼠的病变中未检测到PCSK9蛋白，并且不影响巨噬细胞或脾细胞炎症。总之，PCSK9以低密度脂蛋白依赖而胆固醇独立的机制直接增加动脉粥样硬化病变炎症，这表明治疗性PCSK9抑制可能具有继发于LDL降低的血管益处。
Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) promotes atherosclerosis by increasing low-density lipoprotein (LDL) cholesterol levels through degradation of hepatic LDL receptors (LDLR). Studies have described the systemic effects of PCSK9 on atherosclerosis, but whether PCSK9 has local and direct effects on the plaque in unknown. To study the local effect of human PCSK9 (hPCSK9) on atherosclerotic lesion composition independently of changes in serum cholesterol levels we generated chimeric mice expressing hPCSK9 exclusively from macrophages using marrow from hPCSK9 transgenic (hPCSK9tg) mice transplanted into apoE−/− and LDLR−/− mice, which were then placed on a high fat diet for 8 wk. We further characterized the effect of hPCSK9 expression on the inflammatory responses in the spleen and by mouse peritoneal macrophages (MPM) in vitro. We found that MPM from transgenic mice express both murine (m) Pcsk9 and hPCSK9 and that the latter reduces macrophage LDLR and LRP1 surface levels. hPCSK9 was detected in serum of mice transplanted with hPCSK9tg marrow, but did not influence lipid levels or atherosclerotic lesion size. However, marrow-derived PCSK9 progressively accumulated in lesions of apoE−/− recipient mice while increasing the infiltration of Ly6Chi inflammatory monocytes by 32% compared with controls. Expression of hPCSK9 also increased CD11b and Ly6Chi positive cell numbers in spleens of apoE−/− mice. In vitro, expression of hPCSK9 in LPS-stimulated macrophages increased mRNA levels of the pro-inflammatory markers Tnf and Il1b (40% and 45%, respectively) and suppressed those of the anti-inflammatory markers Il10 and Arg1 (30% and 44%, respectively). All PCSK9 effects were LDLR-dependent as PCSK9 protein was not detected in lesions of LDLR−/− recipient mice and did not affect macrophage or splenocyte inflammation. In conclusion, PCSK9 directly increases atherosclerotic lesion inflammation in an LDLR-dependent but cholesterol-independent mechanism, suggesting that therapeutic PCSK9 inhibition may have vascular benefits secondary to LDL reduction.