Matrix Metalloproteinases Promote Arterial Remodeling in Aging, Hypertension, and Atherosclerosis

摘要

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases, which are highly activated by inflammatory signaling, including that of angiotensin II (Ang II; Figure).1,2 Activated MMPs are able to degrade collagen, elastin, and other extracellular molecules,2 probably resulting in aging, hypertension, and atherosclerotic effects within the arterial wall (for reviews).1,2 The modified extracellular matrix and its context of vasoconstrictors and vasodilators via cleavage by MMPs creates a proinflammatory microenvironment that shifts the phenotypes of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs; for reviews).1,2 These phenotypic shifts in which cells become secretory, migratory, proliferative and senescent facilitate arterial remodeling such as intimal-medial thickening (IMT), fibrosis, calcification, and aneurysms that are associated with a decrease in endothelial-dependent vasodilation and an increase in stiffness (for reviews).1,2 Impressively, MMP inhibition effectively retards/alleviates arterial structural remodeling, decreases stiffness, and improves vascular endothelial function in animal models,3–8 providing a rationale for the translation of MMP actions to therapeutic approaches in aging humans to curb the epidemic of cardiovascular disease.Figure. Matrix metalloproteinase (MMP) activation plays a central role in arterial proinflammatory remodeling and stiffening, which is a structural and functional signature of aging, hypertension, and atherosclerosis. BM indicates basement membrane; EC, endothelial cell; ECM, extracellular matrix; IMT, intimal-medial thickening; and VSMC, vascular smooth muscle cell.MMP activation facilitates arterial remodeling during aging (Figure; Table).View this table:Table. MMP Activation is Involved in Arterial Remodeling and Functional Changes### Endothelial InflammationIncreased MMP activity facilitates endothelial inflammation, such as EC senescence/apoptosisecrosis, thrombosis, and dysfunction (Figure; Table). MMP-1 enhances EC senescence via p53 activation.9 MMP-2 cleaves the intercellular and cell–matrix junctions, including vascular endothelial–cadherin and β- and γ-catenin, which initiates EC apoptosis or necrosis mediated by activated caspase 3, contributing to increased …