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
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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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