Noncanonical Matrix Metalloprotease 1-Protease-Activated Receptor 1 Signaling Drives Progression of Atherosclerosis.
Noncanonical Matrix Metalloprotease 1-Protease-Activated Receptor 1 Signaling Drives Progression of Atherosclerosis.
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DOI：
10.1161/atvbaha.118.310967
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发表时间：
2018-06
期刊：
影响因子：
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通讯作者：
Kuliopulos A
中科院分区：
文献类型：
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作者：
Rana R;Huang T;Koukos G;Fletcher EK;Turner SE;Shearer A;Gurbel PA;Rade JJ;Kimmelstiel CD;Bliden KP;Covic L;Kuliopulos A
蛋白酶激活受体 1 (PAR1) 通常由凝血酶激活，对于控制止血和血栓形成的平衡至关重要。最近，研究表明基质金属蛋白酶 1 (MMP1) 对 PAR1 的非典型激活会导致动脉血栓形成。然而，无论蛋白酶激动剂如何，PAR1 在动脉粥样硬化长期发展中的作用尚不清楚。我们发现，在 91 名接受心导管术或经皮冠状动脉介入治疗的冠状动脉疾病和急性冠状动脉综合征患者中，通过血管造影确定血浆 MMP1 与冠状动脉粥样硬化负荷显着相关（R=0.33；P=0.0015）。细胞穿透性 PAR1 pepducin PZ-128 目前正在 TRIP-PCI 研究（凝血酶受体抑制性 Pepducin-经皮冠状动脉介入治疗）中作为急性环境下的抗血栓剂进行测试，可使总动脉粥样硬化负荷显着降低 58% 至 70%（P<0.05），并将斑块巨噬细胞含量降低 54% (P<0.05) 载脂蛋白 E 缺陷小鼠。 MMP1 抑制剂具有相似的有益效果，而凝血酶抑制剂比伐卢定对动脉粥样硬化终点没有改善。机制研究表明，MMP1-PAR1 介导的炎症信号传导在内皮细胞中放大肿瘤坏死因子 α 信号传导中发挥着关键作用。这些数据表明，靶向 MMP1-PAR1 系统可能有效抑制斑块中的慢性炎症信号传导并阻止动脉粥样硬化的进展。本文提供在线视觉概述。
Protease-activated receptor-1 (PAR1) is classically activated by thrombin and is critical in controlling the balance of hemostasis and thrombosis. More recently, it has been shown that noncanonical activation of PAR1 by matrix metalloprotease-1 (MMP1) contributes to arterial thrombosis. However, the role of PAR1 in long-term development of atherosclerosis is unknown, regardless of the protease agonist. We found that plasma MMP1 was significantly correlated (R=0.33; P=0.0015) with coronary atherosclerotic burden as determined by angiography in 91 patients with coronary artery disease and acute coronary syndrome undergoing cardiac catheterization or percutaneous coronary intervention. A cell-penetrating PAR1 pepducin, PZ-128, currently being tested as an antithrombotic agent in the acute setting in the TRIP-PCI study (Thrombin Receptor Inhibitory Pepducin-Percutaneous Coronary Intervention), caused a significant decrease in total atherosclerotic burden by 58% to 70% (P<0.05) and reduced plaque macrophage content by 54% (P<0.05) in apolipoprotein E–deficient mice. An MMP1 inhibitor gave similar beneficial effects, in contrast to the thrombin inhibitor bivalirudin that gave no improvement on atherosclerosis end points. Mechanistic studies revealed that inflammatory signaling mediated by MMP1–PAR1 plays a critical role in amplifying tumor necrosis factor α signaling in endothelial cells. These data suggest that targeting the MMP1–PAR1 system may be effective in tamping down chronic inflammatory signaling in plaques and halting the progression of atherosclerosis. An online visual overview is available for this article.