Sukhova G K, Schönbeck U, Rabkin E, Schoen F J, Poole A R, Billinghurst R C, Libby P
Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Circulation. 1999 May 18;99(19):2503-9. doi: 10.1161/01.cir.99.19.2503.
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.
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.
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.
最近的几项研究试图将斑块分类为易于引起临床表现的斑块（易损性粥样斑块）或较少与急性血栓并发症相关的斑块（稳定性纤维斑块）。确定这些形态特征背后的细胞和分子机制仍然是一项挑战。由于间质形式的胶原蛋白决定了动脉粥样硬化病变的生物力学强度，本研究调查了人类动脉粥样硬化斑块中胶原蛋白降解基质金属蛋白酶（MMP）间质胶原酶-3（MMP-13）以及先前研究的MMP-1的表达，并使用一种新技术来检验以下假设：粥样硬化病变中的胶原溶解超过人类纤维性动脉粥样硬化病变中的胶原溶解。
将大小相似的人类颈动脉粥样硬化斑块根据传统形态特征分为纤维性病变（n = 10）和粥样性病变（n = 10）。免疫组织化学和蛋白质印迹分析表明，与纤维斑块相比，粥样斑块中MMP-1和MMP-13的水平升高。此外，一种新型的切割特异性抗体显示，胶原酶切割的I型胶原与MMP-1和MMP-13阳性巨噬细胞共定位。巨噬细胞而非内皮细胞或平滑肌细胞在体外刺激时表达MMP-13和MMP-1。此外，蛋白质印迹分析表明，与纤维性病变相比，粥样性病变中I型间质胶原减少，胶原溶解增加。最后，粥样斑块中促炎细胞因子（MMP的激活剂）水平更高。
本报告表明，由于与巨噬细胞相关的胶原溶解增加，可能由间质胶原酶MMP-1和MMP-13介导，粥样斑块而非纤维斑块可能更容易破裂。
