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

Journal of Translational Medicine

Research

Jasmin Hasmik Shahinian¹  Jennifer Esser²  Deepika Gunasekaran³  Agnese Petrera³  Oliver Schilling⁴  Johann Gassenhuber⁵  Sven Ruf⁵  Thomas Hübschle⁵  Thorsten Sadowski⁵  Hartmut Rütten⁵ 

[1]Department of Cardiac Surgery, University Hospital Basel, Spitalstrasse 21, Basel, Switzerland

[2]Department of Cardiology and Angiology, University Heart Center Freiburg, University of Freiburg, Breisacher Strasse 33, 79106, Freiburg, Germany

[3]Institute for Molecular Medicine and Cell Research, University of Freiburg, Stefan Meier Strasse 17, 79104, Freiburg, Germany

[4]Institute for Molecular Medicine and Cell Research, University of Freiburg, Stefan Meier Strasse 17, 79104, Freiburg, Germany

[5]BIOSS Centre for Biological Signaling Studies, University of Freiburg, 79104, Freiburg, Germany

[6]German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

[7]Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65926, Frankfurt Am Main, Germany

关键词: Cardiovascular diseases;    Heart failure;    Myocardial infarction;    Drug therapy;    Mouse model;   

DOI  :  10.1186/s12967-016-0907-8

 received in 2015-12-17, accepted in 2016-05-13,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundMyocardial 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.MethodsMice 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.ResultsCompared 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.ConclusionsOur 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.

【 授权许可】

CC BY   
© The Author(s) 2016