Divergent Roles of Matrix Metalloproteinase 12 in Abdominal Aortic Aneurysms

Abstract

Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteolytic enzymes.In humans, 23 members of MMPs have been identified and 15 of them are observed in the vasculature. 1MMPs degrade many components of the extracellular matrix (ECM), a vital structure in maintaining the integrity of the aortic wall.Thus, MMPs have generated considerable interest in vascular research, particularly in studies of abdominal aortic aneurysms (AAAs) in which ECM degradation is a prominent pathological feature.Among MMPs, several preclinical and clinical studies have investigated the roles of MMP12, initially termed macrophage elastase, in AAAs (Table ). [2][3]3][4] The first report focusing on MMP12 in AAAs was an observational study using human samples. 5MMP12 was upregulated in aneurysmal tissues and localized with elastin fragmentation in the aortic media.The same group subsequently investigated the role of MMP12 by genetic deletion in AAAs formed after elastase infusion in mice. 4Since MMP12 is a potent elastase and exerts a critical role in macrophage-mediated ECM degradation, it was hypothesized that genetic deletion of MMP12 would have protective effects on AAA formation.However, MMP12 did not influence elastase-mediated aneurysm development.Meanwhile, another group reported that MMP12 deletion suppressed CaCl 2 -induced AAAs in mice. 2 The protective effects of MMP12 deletion were also observed in AAAs provoked by simultaneous angiotensin II (AngII) infusion and TGF neutralization. 3Thus, there is inconsistency regarding the impact of MMP12 deletion on development of AAAs.In this issue of Circulation Research, an interesting study by Salarian et al. serendipitously found deleterious effects of MMP12 deletion on AAA formation, 6 which provided new challenges to understanding the role of MMP12 in AAAs.

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