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Published on: September 28, 2015
Metalloproteinase 25 promotes abdominal aortic aneurysm and atherosclerosis
Irene San Sebastian-Jaraba1, Rafael Blázquez-Serra1, Mónica Flores-Muñoz2
1Laboratory for Vascular Biology, IIS-Fundación Jiménez Díaz, Madrid, Spain; CIBERCV, ISCIII, Spain.
Background And Aims:
Matrix metalloproteinases (MMPs) mediate proinflammatory signaling, inflammatory cell recruitment, and extracellular matrix degradation. Involvement of MMPs in the disruption of vascular integrity is implicated in pathologies such as aneurysms and atherosclerosis. This study aimed to elucidate the role of MMP25 in the pathogenesis of abdominal aortic aneurysms (AAA) and atherosclerosis.
Methods:
Wild-type (WT) and Mmp25-/- mice underwent two AAA models: elastase-induced or pAAV/D377Y-mPCSK9 plus AngII infusion. Atherosclerosis was induced using the same adenovirus and a high fat diet for 12 or 20 weeks, generating early or advanced lesions in both genotypes.
Results:
MMP-25 was upregulated in both mouse and human AAA and atherosclerotic plaques. Mmp25-/- mice showed reduced aortic expansion, lesional leukocytes, CD31+ microvessels, chemokine expression, MMP activity, disruption of the elastic layer and increased collagen content than those in WT mice, indicating reduced vascular remodeling in KO animals. Mechanistically, we demonstrate that MMP25 regulates NF-kB activation, TRAF6 and chemokine expression and MMP-9 activity in cultured macrophages and injured aortas. Mmp25-deficient macrophages also showed a diminished migratory capacity under proinflammatory conditions. In addition, Mmp25-deficient mice showed reduced atherosclerotic burden and lesion size in the aortic root compared to WT mice. Plaques from Mmp25-/- mice were characterized by a more stable phenotype with lower lipid and inflammatory content and a smaller necrotic core compared to plaques from WT mice.
Conclusions:
Our data suggest that MMP25 is involved in AAA and atherosclerosis progression. Thus, therapeutic interventions capable of reducing MMP25 expression may delay pathological vascular remodeling.
Insights
Matrix metalloproteinase-25 (MMP25) promotes abdominal aortic aneurysms and atherosclerosis by increasing inflammation and vascular damage. Inhibiting MMP25 may offer a therapeutic strategy to slow disease progression.
Area of Science:
- Vascular Biology
- Immunology
- Matrix Biology
Background:
- Matrix metalloproteinases (MMPs) are key in inflammation and extracellular matrix remodeling, contributing to vascular diseases like aneurysms and atherosclerosis.
- MMP25's specific role in these pathologies remained largely undefined.
Purpose of the Study:
- To investigate the role of MMP25 in the pathogenesis of abdominal aortic aneurysms (AAA) and atherosclerosis.
Main Methods:
- Utilized wild-type and Mmp25 knockout mice in elastase-induced and pAAV/D377Y-mPCSK9 plus AngII infusion models for AAA.
- Induced atherosclerosis using adenovirus and high-fat diet in both genotypes.
- Analyzed vascular remodeling, immune cell infiltration, chemokine expression, and MMP activity.
Main Results:
- MMP25 was upregulated in human and mouse AAA and atherosclerotic plaques.
- Mmp25 knockout mice exhibited reduced aortic expansion, inflammation, microvessel formation, and elastic layer disruption, indicating attenuated vascular remodeling.
- MMP25 deficiency reduced atherosclerotic burden and promoted plaque stability by decreasing lipid and inflammatory content.
Conclusions:
- MMP25 plays a significant role in promoting AAA and atherosclerosis progression.
- Targeting MMP25 could be a therapeutic approach to mitigate pathological vascular remodeling in these diseases.
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