Many Faces of Matrix Metalloproteinases in Aortic Aneurysms

Accumulating evidence links the remodeling of extracellular matrix (ECM) with vascular diseases. In particular, many studies have established the impact of matrix metalloproteinases (MMPs) in various aspects of vascular biology.1 Twenty-three MMP family members are classified into 4 groups: (1) archetypal MMPs, (2) matrilysins, (3) gelatinases, and (4) furin-activated MMPs.2 Archetypal MMPs include 3 collagenases, MMP-1, MMP-8, and MMP-13, major macrophage products that degrade the fibrillar collagens. MMP-collagenases degrade collagen in atherosclerotic lesions3 and may impair the mechanical stability of the plaques, leading to physical disruption (plaque rupture) and acute thrombotic events. After the initial cleavage by collagenases, gelatinases, MMP-2 and MMP-9, degrade collagen fragments, contributing to plaque instability.4 In addition, MMP-2, MMP-9, and MMP-12 (metalloelastase) cleave elastin, another major vascular ECM. Evidence has recognized that elastin degradation by MMPs contributes to the pathogenesis of aortic aneurysms.5 Some cleaved products of ECM are biologically active (matrikines) and promote cell activation and additional monocyte/macrophage infiltration. Thus, MMPs may enhance the positive feedback loop of the proinflammatory milieu in atherosclerotic plaques and aneurysmal aortas.See accompanying article on page 888 Thoracic and abdominal aortic aneurysms (TAA and AAA, respectively) typically show signs of elastin degradation, increased collagen, and accumulation of inflammatory cells. Aneurysmal aortas contain high levels of elastolytic MMP-2, MMP-9, and MMP-12.5 Examining the causal role of each enzyme in vivo typically uses a genetic manipulation and one of the established models of aortic aneurysms, involving systemic infusion of angiotensin II (AngII), or local administration of calcium chloride (CaCl2) or elastase. Several mouse studies demonstrated …