Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms

Abstract

Matrix metalloproteinases (MMPs) 9 and 2 are increased in human abdominal aortic aneurysm (AAA) tissue, but their precise role and potential interaction remain unclear. Experimental induction of aortic aneurysms in mice genetically deficient in these peptidases could provide new insight into AAA pathogenesis. Mice deficient in the expression of MMP-9 (MMP-9KO) or MMP-2 (MMP-2KO) and their corresponding wild-type background mice (WT) underwent AAA induction by abluminal application of calcium chloride (CaCl 2 ). No aneurysm formation was observed at 10 weeks after treatment in either the MMP-9KO or the MMP-2KO mice, whereas the corresponding WT mice showed an average 74% and 52% increase in aortic diameter, respectively. Reinfusion of competent macrophages from the corresponding WT strains into knockout mice resulted in reconstitution of AAA in MMP-9KO but not MMP-2KO mice. These findings suggest that macrophage-derived MMP-9 and mesenchymal cell MMP-2 are both required and work in concert to produce AAA.

A Novel Histone Deacetylase Inhibitor Reduces Abdominal Aortic Aneurysm Formation in Angiotensin II-Infused Apolipoprotein E-Deficient Mice

“…This result confirms previous reports where MMP-2 and MMP-9 may be crucial at the early stages of AAA development in this model [17], and that MCT-1-mediated inhibition of MMP-2 and MMP-9 expression may contribute to the reduction in AAA formation and severity. This is consistent with a previous study that demonstrated that both MMP-2 and MMP-9 knockout mice are resistant to aneurysm development [18]. …”

“…2a, b, fig. 4) protein, previously identified as critical to AAA development [18], was demonstrated with MCT-1 treatment and suggests a mechanistic explanation for reduced AAA incidence and severity identified in MCT-1-treated animals in vivo. In addition, previously described HDACi-mediated inhibition of pro-inflammatory genes [37, 38], implicated in AAA pathogenesis, may also contribute to the mechanism of action of MCT-1 in our study.…”

“…Previous studies have demonstrated that uPA and MMPs play a significant causal role in aortic diameter expansion seen in AAAs [13,14,15,16,17,18]. The current study investigated the influence of a novel HDACi, MCT-1, which has previously been reported to inhibit both uPA and MMP gene transcription in metastatic cancer cells [23], on MMP protein expression and activity in cultured rat and human VSMCs.…”

“…Of the MMPs thought to be involved in the progression of AAAs, MMP-2 and MMP-9 have been the most extensively studied and show strong elastinolytic activity [6,15,16,17]. Both MMP-2 and MMP-9 mRNA are significantly elevated in AAA tissues, and in MMP-2- and MMP-9-knockout mice AAA development is completely abolished [18]. Additionally, in human and animal models of AAAs treatment with a broad-spectrum MMP inhibitor, doxycycline, promotes the preservation of elastin in the vessel wall and also decreases the incidence of AAA formation [19,20,21].…”

Do Extracellular-Matrix-Regulating Enzymes Play a Role in Cervical Artery Dissection?

“…Accelerated matrix breakdown caused by increased activity of MMPs and/or quantitative imbalance between MMP and their inhibitors can result in vascular diseases [1,2,3]. Indeed, increased circulating levels and in situ overexpression of MMP-2, MMP-9 and elastase have been detected in adult humans with aortic and intracranial aneurysms, suggesting an important role for some proteases in arterial wall destruction and resultant aneurysm formation [2,3,4,5,6,7,8,9,10]. These findings raise the possibility that proteases might also be involved in the pathophysiology of spontaneous cervical artery dissection (SCAD), a vascular disease supposed to be related to a yet unidentified ECM defect or fragility [11,12,13,14] and associated with intracranial aneurysms [15, 16].…”