MACROPHAGE FOAM CELLS FROM EXPERIMENTAL ATHEROMA CONSTITUTIVELY PRODUCE MATRIX-DEGRADING PROTEINASES
MACROPHAGE FOAM CELLS FROM EXPERIMENTAL ATHEROMA CONSTITUTIVELY PRODUCE MATRIX-DEGRADING PROTEINASES
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DOI：
10.1073/pnas.92.2.402
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发表时间：
1995-01-17
影响因子：
11.1
通讯作者：
LIBBY, P
中科院分区：
文献类型：
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作者：
GALIS, ZS;SUKHOVA, GK;LIBBY, P
单核细胞来源的泡沫细胞在动脉粥样硬化斑块容易破裂的区域表现突出。培养的外周血单核细胞可以产生某些酶，降解细胞外基质，称为基质金属蛋白酶(MMPs)。因此，富含脂质的巨噬细胞可能导致易破裂的动脉粥样硬化斑块细胞外基质的减弱。然而，泡沫细胞产生基质金属蛋白酶的光谱和调控仍不清楚。为了研究这一问题，我们从高胆固醇血症和球囊损伤所致的兔主动脉损伤中分离出了富含脂质的巨噬细胞。新鲜分离的主动脉巨噬细胞泡沫细胞，用细胞特异性抗体鉴定，含有免疫反应活性的基质溶血素和间质胶原酶，而从同一兔肺分离的肺泡巨噬细胞不含，两种组织来源的巨噬细胞释放的明胶溶解活性与92 kDa明胶酶一致。在体外，在佛波酯或细菌脂多糖的刺激下，载脂的主动脉巨噬细胞，而不是肺泡巨噬细胞，重新合成并释放免疫沉淀的基质分解素和胶原酶。这些刺激导致泡沫细胞释放额外的明胶溶解活性，其迁移速度比含有底物的聚丙烯酰胺凝胶中92 kDa明胶酶的纯化制剂更快，表明92 kDa明胶酶被激活或72 kDa明胶酶被诱导。我们的结果表明，即使在没有进一步刺激的情况下，富含脂质的巨噬细胞也能产生能够降解血管细胞外基质主要成分的MMPs。因此，这些细胞可能有助于动脉粥样硬化形成过程中细胞外基质的重塑和斑块的破坏，这些斑块通常是动脉粥样硬化的急性临床表现。
Monocyte-derived foam cells figure prominently in rupture-prone regions of atherosclerotic plaques. Peripheral blood monocytes in culture can produce certain enzymes that degrade extracellular matrix, known as matrix metalloproteinases (MMPs). Lipid-laden macrophages may thus contribute to weakening of extracellular matrix of rupture-prone atherosclerotic plaques. However, the spectrum and regulation of MMP production by foam cells remain unknown. To investigate this issue, we isolated lipid-laden macrophages from rabbit aortic lesions produced by a combination of hypercholesterolemia and balloon injury. Freshly isolated aortic macrophage foam cells, identified using cell-specific antibodies, contained immunoreactive stromelysin and interstitial collagenase, whereas alveolar macrophages isolated from the lungs of same rabbits did not, Macrophages from both tissue sources released gelatinolytic activity consistent with the 92-kDa gelatinase. In vitro, lipid-laden aortic macrophages, but not alveolar macrophages, synthesized de novo and released immunoprecipitable stromelysin and collagenase, with or without stimulation by phorbol ester or bacterial lipopolysaccharide. These stimuli caused foam cells to release additional gelatinolytic activity that migrated faster than a purified preparation of 92-kDa gelatinase in substrate-containing polyacrylamide gels, indicating activation of the 92-kDa gelatinase or induction of the 72-kDa gelatinase. Our results show that lipid-laden macrophages elaborate MMPs capable of degrading the major constituents of vascular extracellular matrix even without further stimulation. Therefore, these cells may contribute to remodeling of the extracellular matrix during atherogenesis and to the disruption of plaques often responsible for acute clinical manifestations of atherosclerosis.