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Cited by 32Cardiac Fibrosis and RemodelingProtease and Inhibitor MechanismsHeart Failure Treatment and Management

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

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Petrera, Agnese, Gassenhuber, Johann, Ruf, Sven, Gunasekaran, Deepika, Esser, Jennifer, Shahinian, Jasmin Hasmik, Hübschle, Thomas, Rütten, Hartmut +2 more·2016·Journal of Translational Medicine
DOI 10.1186/s12967-016-0907-8PMC PMC4888645
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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.

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  • Increased levels of cathepsin A induced upregulation of cathepsin B, D, and Z and downregulation of numerous protease inhibitors and antioxidative stress proteins in the murine cardiac proteome, and inhibition of cathepsin A activity has cardioprotective properties.

    “Interestingly, increased levels of cathepsin A induced the upregulation of cathepsin B, D and Z, and the downregulation of numerous protease inhibitors, as well as several antioxidative stress proteins 49.”

    From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [50]

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Research works printed but not linked: 33

  1. [1]Bonten EJ Annunziata I d’Azzo A Lysosomal multienzyme complex: pros and cons of working together Cell Mol Life Sci 2014 71 2017 2032 10.1007/s00018-013-1538-3 24337808 PMC4037752 · DOI · Paper page
  2. [2]Hiraiwa M Cathepsin A/protective protein: an unusual lysosomal multifunctional protein Cell Mol Life Sci 1999 56 894 907 10.1007/s000180050482 11212324 PMC11146757 · DOI
  3. [3]Seyrantepe V Hinek A Peng J Fedjaev M Ernest S Kadota Y Enzymatic activity of lysosomal carboxypeptidase (cathepsin) A is required for proper elastic fiber formation and inactivation of endothelin-1 Circulation 2008 117 1973 1981 10.1161/CIRCULATIONAHA.107.733212 18391110 · DOI · Paper page
  4. [4]Petrera A Lai ZW Schilling O Carboxyterminal protein processing in health and disease: key actors and emerging technologies J Proteome Res 2014 13 4497 4504 10.1021/pr5005746 25204196 · DOI
  5. [5]Ruf S Buning C Schreuder H Linz W Hubschle T Linz D Inhibition of CatA: an emerging strategy for the treatment of heart failure Future Med Chem. 2013 5 399 409 10.4155/fmc.13.24 23495688 · DOI
  6. [6]Stanton LW Garrard LJ Damm D Garrick BL Lam A Kapoun AM Altered patterns of gene expression in response to myocardial infarction Circ Res 2000 86 939 945 10.1161/01.RES.86.9.939 10807865 · DOI
  7. [7]Tsukamoto K Mani DR Shi J Zhang S Haagensen DE Otsuka F Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease Proc Natl Acad Sci USA. 2013 110 17023 17028 10.1073/pnas.1315986110 24082102 PMC3801016 · DOI
  8. [8]Ruf S Buning C Schreuder H Horstick G Linz W Olpp T Novel beta-amino acid derivatives as inhibitors of cathepsin A J Med Chem 2012 55 7636 7649 10.1021/jm300663n 22861813 · DOI
  9. [9]Tillner J LA, Paehler T, Lukacs Z, Ruf S, Sadowski T, Pinquier J-L, Ruetten H. Tolerability, safety and pharmacokinetics of the novel Cathepsin A inhibitor SAR164653 in healthy subjects. Clin Pharm Drug Dev. 2015; (in press). 27119579
  10. [10]Heineke J Ruetten H Willenbockel C Gross SC Naguib M Schaefer A Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc Proc Natl Acad Sci USA 2005 102 1655 1660 10.1073/pnas.0405488102 15665106 PMC547821 · DOI
  11. [11]Mendis S Thygesen K Kuulasmaa K Giampaoli S Mahonen M Ngu Blackett K World Health Organization definition of myocardial infarction: 2008-09 revision Int J Epidemiol 2011 40 139 146 10.1093/ije/dyq165 20926369 · DOI
  12. [12]Sun Y Myocardial repair/remodelling following infarction: roles of local factors Cardiovasc Res 2009 81 482 490 10.1093/cvr/cvn333 19050008 PMC2639132 · DOI
  13. [13]Shahinian H Tholen S Schilling O Proteomic identification of protease cleavage sites: cell-biological and biomedical applications Expert Rev Proteomics. 2013 10 421 433 10.1586/14789450.2013.841547 24117201 · DOI
  14. [14]Itter G Jung W Juretschke P Schoelkens BA Linz W A model of chronic heart failure in spontaneous hypertensive rats (SHR) Lab Anim 2004 38 138 148 10.1258/002367704322968812 15070453 · DOI
  15. [15]Tholen S Biniossek ML Gessler AL Muller S Weisser J Kizhakkedathu JN Contribution of cathepsin L to secretome composition and cleavage pattern of mouse embryonic fibroblasts Biol Chem. 2011 392 961 971 10.1515/BC.2011.162 21972973 · DOI
  16. [16]Tholen M Wolanski J Stolze B Chiabudini M Gajda M Bronsert P Stress-resistant translation of cathepsin L mRNA in breast cancer progression J Biol Chem 2015 290 15758 15769 10.1074/jbc.M114.624353 25957406 PMC4505485 · DOI
  17. [17]Lund EL Hog A Olsen MW Hansen LT Engelholm SA Kristjansen PE Differential regulation of VEGF, HIF1alpha and angiopoietin-1, -2 and -4 by hypoxia and ionizing radiation in human glioblastoma Int J Cancer 2004 108 833 838 10.1002/ijc.11662 14712484 · DOI
  18. [18]Patten RD Aronovitz MJ Einstein M Lambert M Pandian NG Mendelsohn ME Effects of angiotensin II receptor blockade versus angiotensin-converting-enzyme inhibition on ventricular remodelling following myocardial infarction in the mouse Clin Sci (Lond). 2003 104 109 118 10.1042/cs1040109 12546633 · DOI
  19. [19]Maisel A B-type natriuretic peptide levels: diagnostic and prognostic in congestive heart failure: what’s next? Circulation 2002 105 2328 2331 10.1161/01.CIR.0000019121.91548.C2 12021215 · DOI
  20. [20]Gaggin HK Januzzi JL Jr Biomarkers and diagnostics in heart failure Biochim Biophys Acta 2013 1832 2442 2450 10.1016/j.bbadis.2012.12.014 23313577 · DOI
  21. [21]Boersema PJ Raijmakers R Lemeer S Mohammed S Heck AJ Multiplex peptide stable isotope dimethyl labeling for quantitative proteomics Nat Protoc 2009 4 484 494 10.1038/nprot.2009.21 19300442 · DOI
  22. [22]Bronsert P Weisser J Biniossek ML Kuehs M Mayer B Drendel V Impact of routinely employed procedures for tissue processing on the proteomic analysis of formalin-fixed paraffin-embedded tissue Proteomics Clin Appl. 2014 8 796 804 10.1002/prca.201300082 24888792 · DOI
  23. [23]Tusher VG Tibshirani R Chu G Significance analysis of microarrays applied to the ionizing radiation response Proc Natl Acad Sci USA 2001 98 5116 5121 10.1073/pnas.091062498 11309499 PMC33173 · DOI · Paper page
  24. [24]Sutton MG Sharpe N Left ventricular remodeling after myocardial infarction: pathophysiology and therapy Circulation 2000 101 2981 2988 10.1161/01.CIR.101.25.2981 10869273 · DOI
  25. [25]Fishbein MC Wang T Matijasevic M Hong L Apple FS Myocardial tissue troponins T and I. An immunohistochemical study in experimental models of myocardial ischemia Cardiovasc Pathol. 2003 12 65 71 10.1016/S1054-8807(02)00188-6 12684160 · DOI
  26. [26]Zhao S Wu H Xia W Chen X Zhu S Zhang S Periostin expression is upregulated and associated with myocardial fibrosis in human failing hearts J Cardiol 2014 63 373 378 10.1016/j.jjcc.2013.09.013 24219836 · DOI
  27. [27]Vaananen HK Syrjala H Rahkila P Vuori J Melamies LM Myllyla V Serum carbonic anhydrase III and myoglobin concentrations in acute myocardial infarction Clin Chem 1990 36 635 638 2108824
  28. [28]Vuotikka P Uusimaa P Niemela M Vaananen K Vuori J Peuhkurinen K Serum myoglobin/carbonic anhydrase III ratio as a marker of reperfusion after myocardial infarction Int J Cardiol 2003 91 137 144 10.1016/S0167-5273(03)00018-4 14559123 · DOI
  29. [29]Carter ND Heath R Jeffery S Jackson MJ Newham DJ Edwards RH Carbonic anhydrase III in Duchenne muscular dystrophy Clin Chim Acta 1983 133 201 208 10.1016/0009-8981(83)90405-9 6414742 · DOI
  30. [30]Razani B Zhang H Schulze PC Schilling JD Verbsky J Lodhi IJ Fatty acid synthase modulates homeostatic responses to myocardial stress J Biol Chem 2011 286 30949 30961 10.1074/jbc.M111.230508 21757749 PMC3162454 · DOI
  31. [31]Singh S Manda SM Sikder D Birrer MJ Rothermel BA Garry DJ Calcineurin activates cytoglobin transcription in hypoxic myocytes J Biol Chem 2009 284 10409 10421 10.1074/jbc.M809572200 19203999 PMC2667728 · DOI
  32. [32]Bonavita F Stefanelli C Giordano E Columbaro M Facchini A Bonafe F H9c2 cardiac myoblasts undergo apoptosis in a model of ischemia consisting of serum deprivation and hypoxia: inhibition by PMA FEBS Lett 2003 536 85 91 10.1016/S0014-5793(03)00029-2 12586343 · DOI
  33. [33]Law CH Li JM Chou HC Chen YH Chan HL Hyaluronic acid-dependent protection in H9C2 cardiomyocytes: a cell model of heart ischemia-reperfusion injury and treatment Toxicology 2013 303 54 71 10.1016/j.tox.2012.11.006 23178681 · DOI

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Authors
Petrera, A., Gassenhuber, J., Ruf, S., Gunasekaran, D., Esser, J., Shahinian, J. H., Hübschle, T., Rütten, H., Sadowski, T., & Schilling, O.
Affiliations
  • University of Freiburg (DE)
  • Sanofi (Germany) (DE)
  • University Hospital of Basel (CH)
Corresponding author
Schilling, Oliver
ORCID
Venue
Journal of Translational Medicine
Publisher
Springer Science and Business Media LLC
Published
2016-05-31
Volume
14
Issue
1
Pages
153-153
ISSN
1479-5876 (ISSN-L)
DOI
10.1186/s12967-016-0907-8
PMC
PMC4888645
OpenAlex
W2409710693
Cited by
32
References
0
Citations by year
2026: 4 · 2025: 5 · 2024: 4 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 3 · 2018: 2 · 2017: 2 · 2016: 2
FWCI
2.06
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Translational Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (SCHI 871/2 and SCHI 871/5, SCHI 871/6, GR 1748/6, and INST 39/900-1)
  • European Research Council (ERC-2011- StG 282111-ProteaSys)
  • Excellence Initiative of the German Federal and State Governments (EXC 294, BIOSS)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
Keywords
cathepsin A, myocardial infarction, heart failure, cardiac proteome, brain natriuretic peptide, cardioprotection, extracellular matrix proteins, left anterior descending artery ligation, fatty acid synthase, IgG2b
MeSH terms
Animals, Cell Line, Disease Models, Animal, Heart Failure, Heart Ventricles, Ligation, Male, Mice, Inbred C57BL, Myocardial Infarction, Organ Size, Peptide Mapping, Protease Inhibitors, Proteome, Proteomics, Cathepsin A, Rats

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