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01.12.2016 | Research | Ausgabe 1/2016 Open Access

Journal of Translational Medicine 1/2016

Cathepsin A inhibition attenuates myocardial infarction-induced heart failure on the functional and proteomic levels

Zeitschrift:
Journal of Translational Medicine > Ausgabe 1/2016
Autoren:
Agnese Petrera, Johann Gassenhuber, Sven Ruf, Deepika Gunasekaran, Jennifer Esser, Jasmin Hasmik Shahinian, Thomas Hübschle, Hartmut Rütten, Thorsten Sadowski, Oliver Schilling
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Electronic supplementary material

The online version of this article (doi:10.​1186/​s12967-016-0907-8) contains supplementary material, which is available to authorized users.

Abstract

Background

Myocardial infarction (MI) is a major cause of heart failure. The carboxypeptidase cathepsin A is a novel target in the treatment of cardiac failure. We aim to show that recently developed inhibitors of the protease cathepsin A attenuate post-MI heart failure.

Methods

Mice were subjected to permanent left anterior descending artery (LAD) ligation or sham operation. 24 h post–surgery, LAD-ligated animals were treated with daily doses of the cathepsin A inhibitor SAR1 or placebo. After 4 weeks, the three groups (sham, MI-placebo, MI-SAR1) were evaluated.

Results

Compared to sham-operated animals, placebo-treated mice showed significantly impaired cardiac function and increased plasma BNP levels. Cathepsin A inhibition prevented the increase of plasma BNP levels and displayed a trend towards improved cardiac functionality. Proteomic profiling was performed for the three groups (sham, MI-placebo, MI-SAR1). More than 100 proteins were significantly altered in placebo-treated LAD ligation compared to the sham operation, including known markers of cardiac failure as well as extracellular/matricellular proteins. This ensemble constitutes a proteome fingerprint of myocardial infarction induced by LAD ligation in mice. Cathepsin A inhibitor treatment normalized the marked increase of the muscle stress marker CA3 as well as of Igγ 2b and fatty acid synthase. For numerous further proteins, cathepsin A inhibition partially dampened the LAD ligation-induced proteome alterations.

Conclusions

Our proteomic and functional data suggest that cathepsin A inhibition has cardioprotective properties and support a beneficial effect of cathepsin A inhibition in the treatment of heart failure after myocardial infarction.
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