Department of Pharmacology, Cardiovascular Research Centre, 4-62 Heritage Medical Research Centre, Univ. of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
Curr Drug Targets. 2013 Mar;14(3):335-43. doi: 10.2174/1389450111314030005.
A group of proteases, the matrix metalloproteinases (MMPs) are well known for their capacity to degrade extracellular matrix (ECM) proteins. Particularly MMP-2 and MMP-9 contribute to the degradation and reorganization of the ECM components and are involved in the pathophysiology of cardiovascular remodeling. Imbalanced MMP activity promotes vascular smooth muscle cells and migration and proliferation and endothelial dysfunction, thus resulting in increased cardiovascular stiffness and hypertrophy. Furthermore, MMP-2 cleaves non-ECM protein substrates including cellular receptors and intracellular proteins, thus causing cardiac and vascular dysfunction. It is now becoming clear that increased MMP activity promotes long-lasting cardiovascular structural and functional alterations in both experimental and clinical hypertension, and this alteration may contribute to sustained hypertension and its complications. Other pathogenic mechanisms including activation of the renin-angiotensin-aldosterone system and oxidative stress activate and upregulate MMPs. Therefore, MMP inhibition may prevent the deleterious consequences of hypertension to the cardiovascular system. This review article will focus on growing evidence supporting the relevance of MMPs in hypertension and the effects of MMP inhibitors. Particularly, the effects of doxycycline used as a non selective MMP inhibitor in experimental and clinical studies will be discussed.
一组蛋白酶，即基质金属蛋白酶（MMPs），以其降解细胞外基质（ECM）蛋白的能力而闻名。特别是 MMP-2 和 MMP-9 有助于 ECM 成分的降解和重组，并参与心血管重构的病理生理学。MMP 活性失衡促进血管平滑肌细胞迁移、增殖和内皮功能障碍，从而导致心血管僵硬和肥大增加。此外，MMP-2 还能切割非 ECM 蛋白底物，包括细胞受体和细胞内蛋白，从而导致心脏和血管功能障碍。现在越来越清楚的是，增加的 MMP 活性在实验性和临床高血压中促进了持久的心血管结构和功能改变，这种改变可能导致持续的高血压及其并发症。其他致病机制，包括肾素-血管紧张素-醛固酮系统的激活和氧化应激，会激活和上调 MMPs。因此，MMP 抑制可能会防止高血压对心血管系统的有害影响。这篇综述文章将重点介绍越来越多的证据支持 MMP 在高血压中的相关性以及 MMP 抑制剂的作用。特别讨论了多西环素作为非选择性 MMP 抑制剂在实验和临床研究中的作用。
