1. Cathepsin A inhibition attenuates myocardial infarction-induced heart failure on the functional and proteomic levels.
- Author
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Petrera, Agnese, Gassenhuber, Johann, Ruf, Sven, Gunasekaran, Deepika, Esser, Jennifer, Shahinian, Jasmin Hasmik, Hübschle, Thomas, Rütten, Hartmut, Sadowski, Thorsten, and Schilling, Oliver
- Subjects
MYOCARDIAL infarction ,HEART failure ,CARBOXYPEPTIDASES ,ARTERIES ,CATHEPSINS ,MYOCARDIAL infarction complications ,THERAPEUTIC use of protease inhibitors ,ANIMAL experimentation ,ANIMALS ,ANTHROPOMETRY ,BIOLOGICAL models ,CELL lines ,HEART ventricles ,LIGATURE (Surgery) ,MICE ,PAPER chromatography ,PEPTIDES ,PROTEOLYTIC enzymes ,RATS ,PROTEOMICS ,PROTEASE inhibitors ,CHEMICAL inhibitors ,PHARMACODYNAMICS - 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. [ABSTRACT FROM AUTHOR]- Published
- 2016
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