Laboratory of Cardiovascular Pathology, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Marlborough Street, BS2 8HW, United Kingdom.
Eur J Pharmacol. 2017 Dec 5;816:93-106. doi: 10.1016/j.ejphar.2017.09.007. Epub 2017 Sep 9.
Atherosclerosis underlies most cardiovascular diseases, and is accepted as a primary cause of mortality worldwide. Proteases have been implicated in the development and progression of atherosclerosis, due to their ability to provoke focal destruction of the vascular extracellular matrix. Members of the metalloproteinase family, especially matrix metalloproteinases (MMPs), and their endogenous tissue inhibitors (TIMPs) have been suggested to perform complex dual roles during late-stage progression and rupture of atherosclerotic plaques. Proposed favourable actions of metalloproteinases include the promotion of vascular smooth muscle growth and survival which stabilises plaques, while conversely extracellular matrix destruction alongside interminable monocyte/macrophage accumulation can encourage plaque rupture. This review provides a summary of the cogent evidence connecting the contribution of individual metalloproteinases to atherosclerotic plaque development, progression, and instability. Topics discussed include structural, functional and cell-specific diversity of MMP members; evidence from animal models of atherosclerosis and comparisons with findings in humans; the dual role of MMPs and the requirement to selectively target individual MMPs; and the need for efficient surrogate markers of MMP inhibition. Accordingly, as our knowledge of the complex roles individual MMPs play especially during the progression and rupture of atherosclerotic plaques expands, new impetus is required for clinical trials evaluating the therapeutic potential of selective MMP inhibition, which could limit cardiovascular morbidity and mortality worldwide.
动脉粥样硬化是大多数心血管疾病的基础，被认为是全球死亡的主要原因。蛋白酶在动脉粥样硬化的发生和发展中起作用，因为它们能够引发血管细胞外基质的局灶性破坏。金属蛋白酶家族的成员，特别是基质金属蛋白酶（MMPs）及其内源性组织抑制剂（TIMPs），在动脉粥样硬化斑块的晚期进展和破裂过程中被认为具有复杂的双重作用。金属蛋白酶的有利作用包括促进血管平滑肌的生长和存活，从而稳定斑块，而相反，细胞外基质的破坏以及无休止的单核细胞/巨噬细胞积累会促进斑块破裂。这篇综述总结了将特定金属蛋白酶与动脉粥样硬化斑块的发展、进展和不稳定性联系起来的有力证据。讨论的主题包括 MMP 成员的结构、功能和细胞特异性多样性；动脉粥样硬化动物模型的证据与人类研究结果的比较；MMP 的双重作用以及需要有针对性地靶向特定 MMP；以及 MMP 抑制的有效替代标志物的需求。因此，随着我们对特定 MMP 在动脉粥样硬化斑块的进展和破裂过程中所起的复杂作用的认识不断加深，需要开展新的临床试验来评估选择性 MMP 抑制的治疗潜力，这可能会限制全球心血管发病率和死亡率。
