Cathepsin A inhibition attenuates myocardial infarction-induced heart failure on the functional and proteomic levels
| Autor: | Petrera, Agnese, Gassenhuber, Johann, Ruf, Sven, Gunasekaran, Deepika, Esser, Jennifer, Shahinian, Jasmin Hasmik, Hübschle, Thomas, Rütten, Hartmut, Sadowski, Thorsten, Schilling, Oliver |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Medicine(all)
Heart Failure Male Proteomics Proteome Biochemistry Genetics and Molecular Biology(all) Research Heart Ventricles Myocardial Infarction Cathepsin A Organ Size Peptide Mapping Mouse model Cell Line Rats Mice Inbred C57BL Disease Models Animal Cardiovascular diseases cardiovascular system Animals Protease Inhibitors Drug therapy Ligation |
| Zdroj: | Journal of Translational Medicine |
| ISSN: | 1479-5876 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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