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Regulation of matrix metalloproteinases and their inhibitors in the left ventricular myocardium of patients with aortic stenosis

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Abstract

Aortic stenosis (AS) results in myocyte and extracellular matrix remodeling in the human left ventricle (LV). The myocardial renin-angiotensin system is activated and collagens I and III and fibronectin accumulate. We determined the yet unknown regulation of enzymes that control collagen turnover, i.e., LV matrix metalloproteinases (MMP) and their tissue inhibitors (TIMPs) in human AS. We compared LV samples from AS patients undergoing elective aortic valve replacement (n=19) with nonused donor hearts with normal LV function (controls, n=12). MMP-2, MMP-9, MT1-MMP, and extracellular matrix metalloproteinase inducer (EMMPRIN), TIMP-1, TIMP-2, TIMP-3, and TIMP-4 mRNA were quantitated by real-time RCR. MMP-1, MMP-2, MMP-3, TIMP-3, TIMP-4, and EMMPRIN protein were measured by immunoblotting and MMP-9 and TIMP-1 protein by ELISA. Gelatinolytic MMP-2 and MMP-9 activity was measured by zymography. MMP-2 was increased in AS at mRNA, protein, and activity levels (131%, 193%, and 138% of controls). MMP-3 protein (308%) and EMMPRIN mRNA and protein were also upregulated (171% and 200%). In contrast, MMP-1 (37%) and MMP-9 mRNA, protein, and activity (26%, 21%, and 52%) were downregulated. MMP-9 activity was inversely correlated with LV size. TIMP-1 mRNA and protein were decreased (55% and 73%). In contrast, TIMP-2 mRNA (358%), TIMP-3 mRNA and protein (145% and 249%) were increased. TIMP-4 mRNA was not altered, but TIMP-4 protein was upregulated to 350%. Changes were similar in AS patients with normal and impaired LV ejection fraction. The dysregulation of myocardial MMPs and TIMPs in human AS starts at an early disease stage when LV function is still normal. In spite of upregulation of some MMPs the balance between MMP and TIMP is shifted towards MMP inhibition in human AS and may contribute to collagen accumulation.

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Abbreviations

AS :

Aortic valve stenosis

ECM :

Extracellular matrix

EF :

Ejection fraction

EMMPRIN :

Extracellular matrix metalloproteinase inducer

LV :

Left ventricle

LVH :

Left ventricular hypertrophy

MMP :

Matrix metalloproteinase

MT-MMP :

Membrane type matrix metalloproteinase

TGF :

Transforming growth factor

TIMP :

Tissue inhibitors of metalloproteinase

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Acknowledgements

This research was supported by Deutsche Forschungsgemeinschaft Re 662/3-5 and GK 554. We thank Anke Doller for discussion of the TIMP-3 and TIMP-4 3′untranslated regions and Kristin Breitschopf and Esther E.J.M. Creemers for carefully reading the manuscript and for discussions. J.F. is a postdoctoral fellow at the Universitätsmedizin Charité Virchow Klinikum.

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Authors and Affiliations

  1. Cardiology, Campus Virchow, Charité Hospital, Berlin, Germany

    Jens Fielitz

  2. Cardiovascular Disease in Women, Charité Hospital, Center for Cardiovascular Research, Hessische Strasse 3–4, 10115, Berlin, Germany

    Manuela Leuschner, Britta Hannack & Vera Regitz-Zagrosek

  3. Deutsches Herzzentrum DHZB, Berlin, Germany

    Manuela Leuschner, Britta Hannack & Vera Regitz-Zagrosek

  4. Klinik für Herz- Gefäß- und Thoraxchirurgie, Deutsches Herzzentrum DHZB, Berlin, Germany

    Heinz Renee Zurbrügg, Reinhard Pregla, Roland Hetzer & Vera Regitz-Zagrosek

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  1. Jens Fielitz
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Correspondence to Vera Regitz-Zagrosek.

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Fielitz, J., Leuschner, M., Zurbrügg, H.R. et al. Regulation of matrix metalloproteinases and their inhibitors in the left ventricular myocardium of patients with aortic stenosis. J Mol Med 82, 809–820 (2004). https://doi.org/10.1007/s00109-004-0606-4

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