Matrix metalloproteinases: influence on smooth muscle cells and atherosclerotic plaque stability.
Matrix metalloproteinases: influence on smooth muscle cells and atherosclerotic plaque stability.
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DOI：
10.1586/14779072.5.2.265
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发表时间：
2007-03-01
影响因子：
2
通讯作者：
Johnson, Jason Lee
中科院分区：
文献类型：
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作者：
Johnson, Jason Lee
动脉粥样硬化斑块破裂和随后的闭塞性血栓形成是大多数心源性猝死的根本原因。基质金属蛋白酶(MMPs)被认为是通过破坏细胞外基质(ECM)蛋白而导致动脉粥样硬化病变向不稳定表型转化的过程。平滑肌细胞分泌和沉积ECM蛋白，因此被认为对动脉粥样硬化斑块失稳具有保护作用。然而，与炎性细胞(如巨噬细胞)类似，平滑肌细胞释放大量能够消化ECM蛋白的MMPs。因此，动脉粥样硬化斑块中平滑肌细胞和MMPs的相互作用是复杂的，并且还不完全清楚。近年来，随着斑块不稳定动物模型的发展，MMPs及其内源性抑制物(金属蛋白酶组织抑制物)的作用以及它们在斑块失稳过程中对平滑肌行为的影响的研究已经得到了帮助。大量研究表明，MMPs除了对ECM重塑有典型作用外，还可直接调节血管平滑肌的行为，对动脉粥样硬化斑块的稳定性既有有益的影响，也有有害的影响。因此，广谱的基质金属蛋白酶抑制可能会抑制斑块的稳定机制，如平滑肌细胞的生长，同时反过来减缓细胞外基质的破坏和随后的破裂。因此，开发选择性的基质金属蛋白酶抑制剂，消除对平滑肌细胞功能的抑制作用，可能是预防斑块破裂的有用疗法，在这方面，基质金属蛋白酶-12似乎是一个特别有吸引力的靶点。
Atherosclerotic plaque rupture, with subsequent occlusive thrombosis, is the underlying cause of most cases of sudden cardiac death. Matrix metalloproteinases (MMPs) are thought to mediate the progression of stable atherosclerotic lesions to an unstable phenotype that is prone to rupture through the destruction of strength-giving extracellular matrix (ECM) proteins. Smooth muscle cells secrete and deposit ECM proteins and are, therefore, considered protective against atherosclerotic plaque destabilization. However, similar to inflammatory cells (e.g., macrophages), smooth muscle cells release numerous MMPs that are capable of digesting ECM proteins. Thus, the interaction of smooth muscle cells and MMPs in atherosclerotic plaques is complex and not fully understood. Recently, research into the roles of MMPs and their endogenous inhibitors (tissue inhibitors of metalloproteinases), and their effects on smooth muscle behavior during plaque destabilization has been aided by the development of reproducible animal models of plaque instability. A plethora of studies has demonstrated that MMPs directly modulate smooth muscle behavior with both beneficial and deleterious effects on atherosclerotic plaque stability, in addition to their canonical effects on ECM remodeling. Consequently, broad-spectrum MMP inhibition may inhibit plaque-stabilizing mechanisms, such as smooth muscle cell growth, while conversely retarding ECM destruction and subsequent rupture. Hence the development of selective MMP inhibitors, that spare inhibitory effects on smooth muscle cell function, may be useful therapies to prevent plaque rupture and in this regard MMP-12 appears to be a particularly attractive target.