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European Heart Journal Advance Access originally published online on April 12, 2005
European Heart Journal 2005 26(13):1333-1341; doi:10.1093/eurheartj/ehi248
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© The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org

Extracellular matrix remodelling in human aortic valve disease: the role of matrix metalloproteinases and their tissue inhibitors

Olivier Fondard1, Delphine Detaint1, Bernard Iung2, Christine Choqueux1, Homa Adle-Biassette3, Mohamed Jarraya4, Ulrich Hvass5, Jean-Paul Couetil5, Dominique Henin3, Jean-Baptiste Michel1, Alec Vahanian2 and Marie-Paule Jacob1,*

1INSERM U 460, Bâtiment 13, Hôpital Bichat-Claude Bernard, 46 rue Henri Huchard, 75877 Paris Cedex 18, France
2Department of Cardiology, Hôpital Bichat-Claude Bernard, 46 rue Henri Huchard, 75877 Paris Cedex 18, France
3Department of Pathology, Hôpital Bichat-Claude Bernard, 46 rue Henri Huchard, 75877 Paris Cedex 18, France
4Banque de Tissus Humains, Hôpital Saint-Louis, 1 avenue Claude Vellefaux 75475, Paris Cedex 10, France
5Department of Cardiac Surgery, Hôpital Bichat-Claude Bernard, 46 rue Henri Huchard, 75877 Paris Cedex 18, France

Received 1 October 2004; revised 10 February 2005; accepted 3 March 2005; online publish-ahead-of-print 12 April 2005.

* Corresponding author. Tel: +33 1 40 25 86 17; fax: +33 1 40 25 86 02. E-mail address: jacob{at}bichat.inserm.fr

Aims 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.

Methods and 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.

Conclusion 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.

Key Words: Aortic stenosis • Aortic regurgitation • Matrix metalloproteinases • Tissue inhibitor of matrix metalloproteinases • Valves


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