A Role for MMP-10 (Matrix Metalloproteinase-10) in Calcific Aortic Valve Stenosis-Reference-Cited by-同舟云学术

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

Published:2020-05 Issue:5 Volume:40 Page:1370-1382
ISSN:1079-5642
Container-title:Arteriosclerosis, Thrombosis, and Vascular Biology
language:en
Short-container-title:ATVB

Author:

Matilla Lara¹,Roncal Carmen²³,Ibarrola Jaime¹,Arrieta Vanessa¹,García-Peña Amaia¹,Fernández-Celis Amaya¹,Navarro Adela¹,Álvarez Virginia¹,Gainza Alicia¹,Orbe Josune²³,Cachofeiro Victoria³⁴,Zalba Guillermo⁵,Sádaba Rafael¹,Rodríguez José A.²³,López-Andrés Natalia¹⁶

Affiliation:

1. From the Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain (L.M., J.I., V. Arrieta, A.G.-P., A.F.-C., A.N., V. Álvarez, A.G., R.S., N.L.-A.)

2. Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA Universidad de Navarra, IdiSNA, Pamplona, Spain (C.R., J.O., J.A.R.)

3. CIBERCV, Instituto de Salud Carlos III, Madrid, Spain (C.R., J.O., V.C., J.A.R.)

4. Departamento de Fisiología, Facultad Medicina, Universidad Complutense, Instituto de Investigacioón Sanitaria Gregorio Maranñoón (IiSGM), Madrid, Spain (V.C.)

5. Department of Biochemistry and Genetics, University of Navarra, IdiSNA, Pamplona, Spain (G.Z.)

6. Université de Lorraine, INSERM, Centre d’Investigations Cliniques-Plurithématique 1433, UMR 1116, CHRU de Nancy, France (N.L.-A.).

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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