A Role for MMP-10 (Matrix Metalloproteinase-10) in Calcific Aortic Valve Stenosis - Université de Lorraine Access content directly
Journal Articles Arteriosclerosis, Thrombosis, and Vascular Biology Year : 2020

A Role for MMP-10 (Matrix Metalloproteinase-10) in Calcific Aortic Valve Stenosis

Abstract

Objective: Aortic valve (AV) calcification plays an important role in the progression of aortic stenosis (AS). MMP-10 (matrix metalloproteinase-10 or stromelysin-2) is involved in vascular calcification in atherosclerosis. We hypothesize that MMP-10 may play a pathophysiological role in calcific AS. Approach and Results: Blood samples (n=112 AS and n=349 controls) and AVs (n=88) from patients undergoing valve replacement were analyzed. Circulating MMP-10 was higher in patients with AS compared with controls ( P <0.001) and correlated with TNFα (tumor necrosis factor α; r S =0.451; P <0.0001). MMP-10 was detected by immunochemistry in AVs from patients with AS colocalized with aortic valve interstitial cells markers α-SMA (α-smooth muscle actin) and vimentin and with calcification markers Runx2 (Runt-related transcription factor 2) and SRY (sex-determining region Y)-box 9. MMP-10 expression in AVs was further confirmed by RT-qPCR and western blot. Ex vivo, MMP-10 was elevated in the conditioned media of AVs from patients with AS and associated with interleukin-1β (r S =0.5045, P <0.001) and BMP (bone morphogenetic protein)-2 (r S =0.5003, P <0.01). In vitro, recombinant human MMP-10 induced the overexpression of inflammatory, fibrotic, and osteogenic markers (interleukin-1β, α-SMA, vimentin, collagen, BMP-4, Sox9, OPN [osteopontin], BMP-9, and Smad 1/5/8; P <0.05) and cell mineralization in aortic valve interstitial cells isolated from human AVs, in a mechanism involving Akt (protein kinase B) phosphorylation. These effects were prevented by TIMP-1 (tissue inhibitor of metalloproteinases type 1), a physiological MMP inhibitor, or specifically by an anti-MMP-10 antibody. Conclusions: MMP-10, which is overexpressed in aortic valve from patients with AS, seems to play a central role in calcification in AS through Akt phosphorylation. MMP-10 could be a new therapeutic target for delaying the progression of aortic valve calcification in AS.
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Dates and versions

hal-03757466 , version 1 (22-08-2022)

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Lara Matilla, Carmen Roncal, Jaime Ibarrola, Vanessa Arrieta, Amaia García-Peña, et al.. A Role for MMP-10 (Matrix Metalloproteinase-10) in Calcific Aortic Valve Stenosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 2020, 40 (5), pp.1370-1382. ⟨10.1161/ATVBAHA.120.314143⟩. ⟨hal-03757466⟩
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