Activation of matrix-degrading metalloproteinases by mast cell proteases in atherosclerotic plaques
Activation of matrix-degrading metalloproteinases by mast cell proteases in atherosclerotic plaques
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DOI：
10.1161/01.atv.18.11.1707
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发表时间：
1998-11-01
影响因子：
8.7
通讯作者：
George, SJ
中科院分区：
文献类型：
--
作者：
Johnson, JL;Jackson, CL;George, SJ
最近的研究表明，肥大细胞来源的中性蛋白酶可以激活基质降解金属蛋白酶（MMPs）。我们研究了肥大细胞蛋白酶类胰蛋白酶和糜蛋白酶在人颈动脉内膜切除术标本（动脉粥样硬化，n=32）和死后颈动脉（对照，n=17）中激活MMPs的作用。在体外脱颗粒的肥大细胞在动脉粥样硬化的颈动脉中的化合物48/80引起MMP活性的显着增加。加入非选择性类胰蛋白酶抑制剂antipain、特异性胰蛋白酶样蛋白酶抑制剂4-amidinophenylmethanesulfonyl fluoride和糜蛋白酶抑制剂chymostatin分别使MMP活性的增加降低了30+/-6%，23 +/-6%，9 +/-2%。免疫细胞化学发现，与对照动脉的图尼卡中膜相比，在动脉粥样硬化动脉病变的“肩”区域中，含类胰蛋白酶的细胞（肥大细胞）和表达MMP-1和MMP-3的细胞数量显著增加。双重免疫细胞化学显示MMP-1和MMP-3与肩部肥大细胞配位。在该区域78+/-5%（平均值+/-SEM）的肥大细胞中观察到脱粒，而在所有其他区域均观察到非活化肥大细胞。原位酶谱显示，在这些领域的酪蛋白和明胶分解活性。总之，在体外肥大细胞脱颗粒，释放肥大细胞蛋白酶，在颈动脉增加MMP活性。此外，MMP-1和MMP-3表达升高与脱颗粒肥大细胞数量增加和动脉粥样硬化斑块肩部区域MMP活性增加相关。肥大细胞源性蛋白酶激活基质金属蛋白酶可能是动脉粥样硬化斑块不稳定的重要机制。
Recent studies suggest that mast cell-derived neutral proteases can activate matrix-degrading metalloproteinases (MMPs). We have investigated the role of the mast cell proteases tryptase and chymase in the activation of MMPs in human carotid endarterectomy specimens (atherosclerotic, n=32) and postmortem carotid arteries (control, n=17). In vitro degranulation of mast cells in atherosclerotic carotid arteries by compound 48/80 caused a significant increase in MMP activity. Addition of the nonselective tryptase inhibitor antipain, the specific trypsinlike protease inhibitor 4-amidinophenylmethanesulfonyl fluoride, and the chymase inhibitor chymostatin reduced this increase in MMP activity by 30+/-6%, 23+/-6%, and 9+/-2%, respectively. Immunocytochemistry identified significantly higher numbers of tryptase-containing cells (mast cells) and cells expressing MMP-1 and MMP-3 in the "shoulder" regions of atherosclerotic artery lesions compared with the tunica media of control arteries. Dual immunocytochemistry showed collocation of MMP-1 and MMP-3 with mast cells in the shoulder regions. Degranulation was observed in 78+/-5% (mean+/-SEM) of mast cells in this area, whereas nonactivated mast cells were observed in all other areas. In situ zymography revealed caseinolytic and gelatinolytic activity in these areas. In conclusion, in vitro mast cell degranulation, which releases mast cell proteases, in carotid arteries increases MMP activity. Furthermore, elevated MMP-1 and MMP-3 expression is collocated with increased numbers of degranulated mast cells and with greater MMP activity in the shoulder regions of atherosclerotic plaques. Activation of MMPs by mast cell-derived proteases may be an important mechanism in atherosclerotic plaque destabilization.