N-acetyl-cysteine decreases the matrix-degrading capacity of macrophage-derived foam cells - New target for antioxidant therapy?
N-acetyl-cysteine decreases the matrix-degrading capacity of macrophage-derived foam cells - New target for antioxidant therapy?
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DOI：
10.1161/01.cir.97.24.2445
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发表时间：
1998-06-23
期刊：
影响因子：
37.8
通讯作者：
Meng, XP
中科院分区：
文献类型：
--
作者：
Galis, ZS;Asanuma, K;Meng, XP
背景-动脉粥样硬化斑块不稳定触发临床心血管疾病，因此代表了一个有吸引力的治疗靶点。削弱组织通过行动的基质降解酶，称为基质金属蛋白酶（MMPs），由居民巨噬细胞释放以前牵连在不稳定的血管syndrome.Methods和Results-We使用高胆固醇血症兔动脉粥样硬化模型，调查明胶分解活性与巨噬细胞衍生的泡沫细胞（FC）。明胶溶解活性和MMP-9的表达，而不是MMP-2与主动脉病变中的巨噬细胞FC共分离。在体外进一步研究了巨噬细胞来源的明胶酶。MMP-9被鉴定为从主动脉病变和从在相同兔中诱导的肉芽肿中分离的细胞中的主要巨噬细胞来源的明胶酶，以增加细胞产量。重要的是，在FC培养基中检测到活化的MMP-9支持了这些细胞可以独立地启动分泌的MMP酶原加工成活性酶的观点。我们进一步研究了FC明胶分解活性是否依赖于活性氧（ROS）的存在。我们发现，处理（1至5天）与1至10 mmol/L的N-乙酰-L-半胱氨酸（NAC），活性氧清除剂，不仅降低明胶分解活性，但也明胶酶的表达FC。同样地，NAC治疗的acromuted病变废除原位明胶分解活性和MMP-9 expressions.Conclusions-Macrophage FCs是一个丰富的来源明胶分解活性，可以抑制在体外和原位NAG。这种新描述的抗氧化治疗作用可能被证明对抑制基质降解和改善血管稳定性有用。
Background-Atherosclerotic plaque destabilization triggers clinical cardiovascular disease and thus represents an attractive therapeutic target. Weakening of tissue through the action of matrix-degrading enzymes, called matrix metalloproteinases (MMPs), released by resident macrophages was previously implicated in unstable vascular syndromes.Methods and Results-We used a hypercholesterolemic rabbit model of atherosclerosis to investigate the gelatinolytic activity associated with macrophage-derived foam cells (FCs). Gelatinolytic activity and expression of MMP-9 but not of MMP-2 cosegregated with macrophage FCs in aortic lesions. Macrophage-derived gelatinases were further investigated in vitro. MMP-9 was identified as the main macrophage-derived gelatinase in cells isolated from aortic lesions and from granuloma induced in the same rabbits to increase cell yield. Importantly, detection of activated MMP-9 in the FC culture medium supports the notion that these cells can independently initiate processing of secreted MMP zymogens to active enzymes. We further examined whether FC gelatinolytic activity is dependent on the presence of reactive oxygen species (ROS). We found that treatment (1 to 5 days) with 1 to 10 mmol/L N-acetyl-L-cysteine (NAC), an ROS scavenger, decreased not only gelatinolytic activity but also gelatinase expression by FCs. Similarly, NAC treatment of explanted lesions abolished in situ gelatinolytic activity and MMP-9 expression.Conclusions-Macrophage FCs are an abundant source of gelatinolytic activity that can be inhibited in vitro and in situ by NAG. This newly described action of antioxidant therapy might prove useful to inhibit matrix degradation and to improve vascular stability.