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

Arterioscler Thromb Vasc Biol. 2020 May;40(5):1370-1382. doi: 10.1161/ATVBAHA.120.314143. Epub 2020 Mar 19.

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; rS=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 (rS=0.5045, P<0.001) and BMP (bone morphogenetic protein)-2 (rS=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.

Keywords: aortic valve stenosis; blotting, Western; collagen; inflammation; interleukin-1.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aortic Valve / enzymology*
  • Aortic Valve / pathology*
  • Aortic Valve Stenosis / enzymology*
  • Aortic Valve Stenosis / genetics
  • Aortic Valve Stenosis / pathology
  • Calcinosis / enzymology*
  • Calcinosis / genetics
  • Calcinosis / pathology
  • Case-Control Studies
  • Cells, Cultured
  • Female
  • Fibrosis
  • Humans
  • Inflammation Mediators / metabolism
  • Male
  • Matrix Metalloproteinase 10 / genetics
  • Matrix Metalloproteinase 10 / metabolism*
  • Middle Aged
  • Osteogenesis* / genetics
  • Phosphorylation
  • Prospective Studies
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Up-Regulation

Substances

  • Inflammation Mediators
  • Proto-Oncogene Proteins c-akt
  • MMP10 protein, human
  • Matrix Metalloproteinase 10

Supplementary concepts

  • Aortic Valve, Calcification of