Oxidized Low-Density Lipoprotein Induces Macrophage Production of Prothrombotic Microparticles.
Oxidized Low-Density Lipoprotein Induces Macrophage Production of Prothrombotic Microparticles.
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氧化低密度脂蛋白诱导巨噬细胞产生血栓前微粒。
DOI：
10.1161/jaha.120.015878
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发表时间：
2020-08-04
影响因子：
5.4
通讯作者：
Croce K
中科院分区：
文献类型：
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作者：
Marchini JF;Manica A;Crestani P;Dutzmann J;Folco EJ;Weber H;Libby P;Croce K
活化的血管细胞产生亚微米促血栓形成和促炎微粒囊泡。动脉粥样硬化斑块含有高水平的微粒。急性冠状动脉综合征期间血浆微粒水平增加，斑块破裂的血栓形成后果可能涉及巨噬细胞衍生微粒（MΦ MP）。促进MΦMP产生的活化途径仍然不清楚。本研究验证了动脉粥样硬化形成相关信号也刺激MΦMP产生的假设。我们用促炎细胞因子和致动脉粥样硬化脂质刺激人原代MΦ，并通过流式细胞术测量MΦMP的产生。氧化低密度脂蛋白（oxLDL; 25 µg/mL）以浓度依赖性方式诱导MΦMP产生（增加293%; P<0.001），这些oxLDL MΦMP刺激作用由CD 36介导。oxLDL刺激使MΦMP组织因子含量增加78%（P<0.05），oxLDL诱导的MΦMP产生与caspase 3/7信号通路的激活相关。丹酚酸B（一种CD 36抑制剂）和CD 36抑制剂抗体分别使oxLDL诱导的MΦMP降低67%和60%。Caspase 3/7抑制使MΦMP释放减少52%（P<0.01），Caspase 3/7激活使MΦMP释放增加208%（P<0.01）。美伐他汀预处理（10 µM）可降低oxLDL诱导的caspase 3/7活化，并使oxLDL刺激的MΦMP产生和组织因子含量分别减少60%（P<0.01）和43%（P<0.05）。OxLDL诱导巨噬细胞中血栓前微粒的产生。这一过程依赖于半胱天冬酶3和7以及CD 36，并被美伐他汀预处理抑制。这些发现将致动脉粥样硬化信号通路、炎症和斑块血栓形成联系起来，并确定了他汀类药物不依赖于LDL降低的抗血栓形成作用的新的潜在机制。
Activated vascular cells produce submicron prothrombotic and proinflammatory microparticle vesicles. Atherosclerotic plaques contain high levels of microparticles. Plasma microparticle levels increase during acute coronary syndromes and the thrombotic consequences of plaque rupture likely involve macrophage‐derived microparticles (MΦMPs). The activation pathways that promote MΦMP production remain poorly defined. This study tested the hypothesis that signals implicated in atherogenesis also stimulate MΦMP production. We stimulated human primary MΦs with proinflammatory cytokines and atherogenic lipids, and measured MΦMP production by flow cytometry. Oxidized low‐density lipoprotein (oxLDL; 25 µg/mL) induced MΦMP production in a concentration‐dependent manner (293% increase; P<0.001), and these oxLDL MΦMP stimulatory effects were mediated by CD36. OxLDL stimulation increased MΦMP tissue factor content by 78% (P<0.05), and oxLDL‐induced MΦMP production correlated with activation of caspase 3/7 signaling pathways. Salvionolic acid B, a CD36 inhibitor and a CD36 inhibitor antibody reduced oxLDL‐induced MΦMP by 67% and 60%, respectively. Caspase 3/7 inhibition reduced MΦMP release by 52% (P<0.01) and caspase 3/7 activation increased MΦMP production by 208% (P<0.01). Mevastatin pretreatment (10 µM) decreased oxLDL‐induced caspase 3/7 activation and attenuated oxLDL‐stimulated MΦMP production and tissue factor content by 60% (P<0.01) and 43% (P<0.05), respectively. OxLDL induces the production of prothrombotic microparticles in macrophages. This process depends on caspases 3 and 7 and CD36 and is inhibited by mevastatin pretreatment. These findings link atherogenic signaling pathways, inflammation, and plaque thrombogenicity and identify a novel potential mechanism for antithrombotic effects of statins independent of LDL lowering.