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

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.

• Authors: Agnese Petrera, Johann Gassenhuber, Sven Ruf, Deepika Gunasekaran, Jennifer Esser, Jasmin Hasmik Shahinian, Thomas Hübschle, Hartmut Rütten, Thorsten Sadowski, Oliver Schilling
• Journal: Journal of translational medicine (J Transl Med) Vol. 14 Issue 1 Pg. 153 (05 31 2016) ISSN: 1479-5876 [Electronic] England
• PMID: 27246731 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protease Inhibitors
• Proteome
• Cathepsin A

Topics

• Animals
• Cathepsin A (antagonists & inhibitors, metabolism)
• Cell Line
• Disease Models, Animal
• Heart Failure (drug therapy, etiology, metabolism, physiopathology)
• Heart Ventricles (drug effects, pathology)
• Ligation
• Male
• Mice, Inbred C57BL
• Myocardial Infarction (complications, drug therapy, metabolism, physiopathology)
• Organ Size (drug effects)
• Peptide Mapping
• Protease Inhibitors (pharmacology, therapeutic use)
• Proteome (metabolism)
• Proteomics (methods)
• Rats