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Reduced MMP-2 activity contributes to cardiac fibrosis in experimental diabetic cardiomyopathy

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Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Objective

To evaluate the regulation of matrix metalloproteinase (MMP)-2 in diabetic cardiomyopathy.

Methods

Left ventricle (LV) function was determined by a micro-tip catheter in streptozotocin (STZ)-induced diabetic rats, 2 or 6 weeks (w) after STZ-application. LV total collagen, collagen type I and III content were immunohistologically analyzed and quantified by digital image analysis. LV collagen type I, III and MMP-2 mRNA expression was quantified by real-time RT-PCR. LV pro- and active MMP-2 levels were analyzed by zymography; Smad 7, membrane type (MT)1-MMP and tissue inhibitor metalloproteinase (TIMP)-2 protein levels by Western Blot.

Results

STZ-induced diabetes was associated with a time-dependent impairment of LV diastolic and systolic function. This was paralleled by a time-dependent increase in LV total collagen content, despite reduced LV collagen type I and III mRNA levels, indicating a role of post-transcriptional/post-translational changes of extracellular matrix regulation. Six weeks (w) after STZ-injection, MMP-2 mRNA expression and pro-MMP-2 levels were 2.7-fold (P < 0.005) and 1.3-fold (P < 0.05) reduced versus controls, respectively, whereas active MMP-2 was decreased to undetectable levels 6 w post-STZ. Concomitantly, Smad 7 and TIMP-2 protein levels were 1.3-fold (P < 0.05) and 10-fold (P < 0.005) increased in diabetics versus controls, respectively, whereas the 45 kDa form of MT1-MMP was undetectable in diabetics.

Conclusion

Under STZ-diabetic conditions, cardiac fibrosis is associated with a dysregulation in extracellular matrix degradation. This condition is featured by reduced MMP-2 activity, concomitant with increased Smad 7 and TIMP-2 and decreased MT1-MMP protein expression, which differs from mechanisms involved in dilated and ischemic heart disease.

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Acknowledgments

This study was supported by the DFG (TR SFB19 B5, A21) to CT and MP and by the Bundesministerium für Bildung und Forschung (Competence Network of Heart Failure) to MB; US.

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Authors and Affiliations

  1. Dept. of Cardiology and Pneumology, Charité-University Medicine Berlin, Campus Benjamin Franklin Hindenburgdamm 30, 12200, Berlin, Germany

    Sophie Van Linthout, Alexander Riad, Oleg Eckhardt, Nasser Dhayat, Utz Richter, Matthias Pauschinger, Heinz-Peter Schultheiss & Carsten Tschöpe MD

  2. Dept. of Cardiology/Angiology, University-Clinic of Saarland, Internal Medicine III, Homburg/Saar, Germany

    Ute Seeland, Mathias Hohl & Michael Böhm

  3. Molecular Pharmacology, Institute of Pharmacology and Clinical Pharmacology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

    Jens W. Fischer

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  1. Sophie Van Linthout
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Corresponding author

Correspondence to Carsten Tschöpe MD.

Additional information

Sophie Van Linthout and Ute Seeland contributed equally.

Returned for 1. Revision: 24 October 2007 1. Revision received: 21 December 2007

Returned for 2. Revision: 7 January 2008 2. Revision received: 17 January 2008

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Van Linthout, S., Seeland, U., Riad, A. et al. Reduced MMP-2 activity contributes to cardiac fibrosis in experimental diabetic cardiomyopathy. Basic Res Cardiol 103, 319–327 (2008). https://doi.org/10.1007/s00395-008-0715-2

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