title: Cathepsin A inhibition attenuates myocardial infarction-induced heart failure on the functional and proteomic levels.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Institute for Molecular Medicine and Cell Research, University of Freiburg, Stefan Meier Strasse 17, 79104, Freiburg, Germany.
authors.forename: Agnese
authors.initials: A
authors.lastname: Petrera
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65926, Frankfurt Am Main, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Gassenhuber
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65926, Frankfurt Am Main, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Ruf
authors.affiliation: Institute for Molecular Medicine and Cell Research, University of Freiburg, Stefan Meier Strasse 17, 79104, Freiburg, Germany.
authors.forename: Deepika
authors.initials: D
authors.lastname: Gunasekaran
authors.affiliation: Department of Cardiology and Angiology, University Heart Center Freiburg, University of Freiburg, Breisacher Strasse 33, 79106, Freiburg, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Esser
authors.affiliation: Department of Cardiac Surgery, University Hospital Basel, Spitalstrasse 21, Basel, Switzerland.
authors.forename: Jasmin Hasmik
authors.initials: JH
authors.lastname: Shahinian
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65926, Frankfurt Am Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hübschle
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65926, Frankfurt Am Main, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Rütten
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65926, Frankfurt Am Main, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Sadowski
authors.affiliation: Institute for Molecular Medicine and Cell Research, University of Freiburg, Stefan Meier Strasse 17, 79104, Freiburg, Germany. oliver.schilling@mol-med.uni-freiburg.de.|BIOSS Centre for Biological Signaling Studies, University of Freiburg, 79104, Freiburg, Germany. oliver.schilling@mol-med.uni-freiburg.de.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. oliver.schilling@mol-med.uni-freiburg.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Schilling
mesh_terms: D000818:Animals; D043402:Cathepsin A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D008026:Ligation; D008297:Male; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009929:Organ Size / Q000187:drug effects; D010449:Peptide Mapping; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D020543:Proteome / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D051381:Rats
chemical_list: D011480:Protease Inhibitors; D020543:Proteome; D043402:Cathepsin A
keywords: Cardiovascular diseases; Drug therapy; Heart failure; Mouse model; Myocardial infarction