Deficiency of MMP1a (Matrix Metalloprotease 1a) Collagenase Suppresses Development of Atherosclerosis in Mice: Translational Implications for Human Coronary Artery Disease.
Deficiency of MMP1a (Matrix Metalloprotease 1a) Collagenase Suppresses Development of Atherosclerosis in Mice: Translational Implications for Human Coronary Artery Disease.
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DOI：
10.1161/atvbaha.120.315837
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发表时间：
2021-05-05
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：
Fletcher EK;Wang Y;Flynn LK;Turner SE;Rade JJ;Kimmelstiel CD;Gurbel PA;Bliden KP;Covic L;Kuliopulos A
动脉胶原的破坏允许单核细胞和巨噬细胞浸润，导致动脉粥样硬化斑块的形成，但目前尚不清楚MMP 1胶原酶在体内这一过程中起什么作用。为了确定MMP 1对动脉粥样硬化斑块负荷和发病机制的具体贡献，我们产生了人类MMP 1直系同源物MMP 1a缺陷的ApoE−/−小鼠。在西方饮食12-16周后，与对照ApoE−/−小鼠相比，MMP 1a的遗传缺失导致总主动脉斑块负荷显著减少50%。MMP 1a缺乏导致斑块单核细胞/巨噬细胞、SMC和坏死显著减少，胶原含量增加。MMP 1a缺陷小鼠的氧化LDL激活的PBMC的胶原侵袭显著减弱，并且与MMP 1及其受体PAR 1的药理学抑制剂的抑制作用相似。对TRIP-PCI试验中接受心导管插入术的CAD和ACS患者的所有3种主要分泌型胶原酶MMP 1、MMP 8和MMP 13的循环水平以及狭窄≥50%的冠状动脉病变总数（CAD负荷）进行了评价。MMP 1分别显著（P<0.001）高于MMP 13和MMP 8 19倍和5.7倍。MMP 1与狭窄CAD负荷、TNFα水平相关，并与单核细胞上的PAR 1共表达。用PAR 1抑制剂PZ-128治疗患者，防止了冠状动脉导管插入术后单核细胞的下降，这是一种急性保护作用，在经历心脏缺血再灌注的小鼠中重现。这些数据为MMP 1a胶原酶在动脉粥样硬化病变发展和白细胞行为中的重要作用提供了证据，并验证了MMP 1作为CAD/ACS患者的一个引人注目的靶点。
Destruction of arterial collagen allows monocyte and macrophage infiltration leading to atherosclerotic plaque formation, but it is not clear what role the MMP1 collagenase plays in this process in vivo. To define the specific contribution of MMP1 to atherosclerotic plaque burden and pathogenesis, we generated ApoE−/− mice deficient in the human MMP1 ortholog, MMP1a. After 12–16 weeks of western diet, genetic loss of MMP1a resulted in a significant 50% reduction in total aortic plaque burden compared to control ApoE−/− mice. MMP1a deficiency led to significant reductions in plaque monocytes/macrophages, SMCs, and necrosis, with increases in collagen content. Collagen invasion of oxidized-LDL activated PBMCs from MMP1a-deficient mice was markedly attenuated and was similar to suppressive effects with pharmacologic inhibitors of MMP1 and its receptor, PAR1. CAD and ACS patients undergoing cardiac catheterization in the TRIP-PCI trial were evaluated for circulating levels of all 3 major secreted collagenases, MMP1, MMP8 and MMP13 and total number of coronary lesions with ≥50% stenosis (CAD burden). MMP1 was significantly (P<0.001) higher by 19-fold and 5.7-fold relative to MMP13 and MMP8, respectively. MMP1 correlated with stenotic CAD burden, TNFα levels, and was co-expressed with PAR1 on monocytes. Treatment of patients with the PAR1 inhibitor, PZ-128, prevented a drop in monocytes following coronary catheterization, an acute protective effect that was reproduced in mice undergoing cardiac ischemia reperfusion. These data provide evidence for an important role for the MMP1a collagenase in atherosclerotic lesion development and leukocyte behavior and validate MMP1 as a compelling target in CAD/ACS patients.