Evidence for increased collagenolysis by interstitial collagenases-1 and-3 in vulnerable human atheromatous plaques
Evidence for increased collagenolysis by interstitial collagenases-1 and-3 in vulnerable human atheromatous plaques
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DOI：
10.1161/01.cir.99.19.2503
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发表时间：
1999-05-18
期刊：
影响因子：
37.8
通讯作者：
Libby, P
中科院分区：
文献类型：
--
作者：
Sukhova, GK;Schönbeck, U;Libby, P
背景-最近的几项研究试图将斑块分类为容易引起临床表现的斑块（脆弱的动脉粥样硬化斑块）或与急性血栓性并发症相关的斑块（稳定的纤维斑块）。确定这些形态特征背后的细胞和分子机制仍然是一个挑战。由于胶原的间质形式决定了动脉粥样硬化病变的生物力学强度，本研究调查了胶原降解基质金属蛋白酶（MMP）、间质胶原酶-3（MMP-13）和先前研究的MMP-1在人类动脉粥样硬化中的表达，并使用一种新的技术来检验动脉粥样硬化病变中胶原溶解超过纤维性人类动脉粥样硬化病变的假设。将大小相似的人颈动脉粥样硬化斑块按常规形态学特征分为纤维性斑块（n=10）和粥样硬化性斑块（n=10）。免疫组化和Western blot分析显示，MMP-1和MMP-13在粥样硬化性斑块中的表达高于纤维性斑块。此外，胶原酶裂解的I型胶原，证明了一种新的裂解特异性抗体，共定位与MMP-1和MMP-13阳性的巨噬细胞，巨噬细胞，而不是内皮细胞或平滑肌细胞，表达MMP-13和MMP-1的刺激在体外，此外，蛋白质印迹分析表明，损失的间质胶原I型和增加的胶原溶解在动脉粥样硬化与纤维病变。最后，动脉粥样硬化斑块含有较高水平的促炎细胞因子，MMPs.Conclusions-This报告的激活剂表明，动脉粥样硬化，而不是纤维斑块可能容易破裂，由于增加胶原溶解与巨噬细胞，可能介导的间质胶原酶MMP-1和MMP-13。
Background-Several recent studies attempted to classify plaques as those prone to cause clinical manifestations (vulnerable, atheromatous plaques) or those less frequently associated with acute thrombotic complication (stable, fibrous plaques). Defining the cellular and molecular mechanisms that underlie these morphological features remains a challenge. Because interstitial forms of collagen determine the biomechanical strength of the atherosclerotic lesion, this study investigated expression of the collagen-degrading matrix metalloproteinase (MMP) interstitial collagenase-3 (MMP-13) and the previously studied MMP-1 in human atheroma and used a novel technique to test the hypothesis that collagenolysis in atheromatous lesions exceeds that in fibrous human atherosclerotic lesions.Methods and Results-Human carotid atherosclerotic plaques, similar in size, were separated by conventional morphological characteristics into fibrous (n=10) and atheromatous (n=10) lesions, Immunohistochemical and Western blot analysis demonstrated increased levels of MMP-1 and MMP-13 in atheromatous versus fibrous plaques. In addition, collagenase-cleaved type I collagen, demonstrated by a novel cleavage-specific antibody, colocalized with MMP-1- and MMP-13-positive macrophages, Macrophages, rather than endothelial or smooth muscle cells, expressed MMP-13 and MMP-1 on stimulation in vitro, Furthermore, Western blot analysis demonstrated loss of interstitial collagen type I and increased collagenolysis in atheromatous versus fibrous lesions. Finally, atheromatous plaques contained higher levels of proinflammatory cytokines, activators of MMPs.Conclusions-This report demonstrates that atheromatous rather than fibrous plaques might be prone to rupture due to increased collagenolysis associated with macrophages, probably mediated by the interstitial collagenases MMP-1 and MMP-13.