Extracellular matrix remodelling in human aortic valve disease: the role of matrix metalloproteinases and their tissue inhibitors.
OBJECTIVE
Aortic valve diseases are characterized by pathological remodelling of valvular tissue but the cellular and molecular effectors involved in these processes are not well known. The role of matrix metalloproteinase (MMP)-2, MMP-9, MMP-3, MMP-7, and tissue inhibitor of matrix metalloproteinase (TIMP)-1 and TIMP-2 are investigated here.


RESULTS
Histological analysis of pathological valves [aortic stenosis (AS) (n=49), aortic regurgitation (AR) (n=23)] and control valves (n=8) was performed. The main tissue abnormalities (calcification, inflammatory cells, and capillaries) observed in AS were less severe or absent in AR. However, both groups of pathological valves displayed similar histological signs of extracellular matrix (ECM) remodelling. Biochemical analysis of MMPs and TIMPs (gelatin and casein zymography and ELISA) was performed on valve extracts. MMP-2 activity was not significantly different in control and pathological valves. Increases in MMP-9 and MMP-3 in AS demonstrated an inflammatory state. Finally, there was a four- to seven-fold increase of TIMP-1 in pathological valves. TIMP-1, TIMP-2, and MMP-2 were synthesized by the valvular interstitial cells in primary culture.


CONCLUSIONS
This study demonstrates the involvement of the MMP/TIMP system in ECM remodelling of both AS and AR. These findings provide evidence of inflammatory injury more severe in AS than in AR and involvement of mesenchymal cell response.
Fondard
Olivier
O
INSERM U 460, Bâtiment 13, Hôpital Bichat-Claude Bernard, 46 rue Henri Huchard, 75877 Paris Cedex 18, France.
Detaint
Delphine
D
Iung
Bernard
B
Choqueux
Christine
C
Adle-Biassette
Homa
H
Jarraya
Mohamed
M
Hvass
Ulrich
U
Couetil
Jean-Paul
JP
Henin
Dominique
D
Michel
Jean-Baptiste
JB
Vahanian
Alec
A
Jacob
Marie-Paule
MP
D000328:Adult; D001022:Aortic Valve Insufficiency / Q000201:enzymology / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000201:enzymology / Q000473:pathology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism / Q000502:physiology*
D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases