TIP30 counteracts cardiac hypertrophy and failure by inhibiting translational elongation.

Abstract

Pathological cardiac overload induces myocardial protein synthesis and hypertrophy, which predisposes to heart failure. To inhibit hypertrophy therapeutically, the identification of negative regulators of cardiomyocyte protein synthesis is needed. Here, we identified the tumor suppressor protein TIP30 as novel inhibitor of cardiac hypertrophy and dysfunction. Reduced TIP30 levels in mice entailed exaggerated cardiac growth during experimental pressure overload, which was associated with cardiomyocyte cellular hypertrophy, increased myocardial protein synthesis, reduced capillary density, and left ventricular dysfunction. Pharmacological inhibition of protein synthesis improved these defects. Our results are relevant for human disease, since we found diminished cardiac TIP30 levels in samples from patients suffering from end-stage heart failure or hypertrophic cardiomyopathy. Importantly, therapeutic overexpression of TIP30 in mouse hearts inhibited cardiac hypertrophy and improved left ventricular function during pressure overload and in cardiomyopathic mdx mice. Mechanistically, we identified a previously unknown anti-hypertrophic mechanism, whereby TIP30 binds the eukaryotic elongation factor 1A (eEF1A) to prevent the interaction with its essential co-factor eEF1B2 and translational elongation. Therefore, TIP30 could be a therapeutic target to counteract cardiac hypertrophy.

• Authors: Andrea Grund, Malgorzata Szaroszyk, Mortimer Korf-Klingebiel, Mona Malek Mohammadi, Felix A Trogisch, Ulrike Schrameck, Anna Gigina, Christopher Tiedje, Matthias Gaestel, Theresia Kraft, Jan Hegermann, Sandor Batkai, Thomas Thum, Andreas Perrot, Cris Dos Remedios, Eva Riechert, Mirko Völkers, Shirin Doroudgar, Andreas Jungmann, Ralf Bauer, Xiaoke Yin, Manuel Mayr, Kai C Wollert, Andreas Pich, Hua Xiao, Hugo A Katus, Johann Bauersachs, Oliver J Müller, Joerg Heineke
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 11 Issue 10 Pg. e10018 (10 2019) ISSN: 1757-4684 [Electronic] England
• PMID: 31468715 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• EEF1A1 protein, human
• Guanine Nucleotide Exchange Factors
• Peptide Elongation Factor 1
• Repressor Proteins
• Tip30 protein, mouse
• Transcription Factors
• Tumor Suppressor Proteins
• eEF1B-beta protein, human
• Acetyltransferases
• HTATIP2 protein, human

Topics

• Acetyltransferases (metabolism)
• Animals
• Cardiomegaly (physiopathology)
• Disease Models, Animal
• Guanine Nucleotide Exchange Factors (metabolism)
• Humans
• Mice
• Mice, Inbred mdx
• Myocytes, Cardiac (metabolism)
• Peptide Chain Elongation, Translational
• Peptide Elongation Factor 1 (metabolism)
• Protein Binding
• Protein Interaction Maps
• Repressor Proteins (metabolism)
• Transcription Factors (metabolism)
• Tumor Suppressor Proteins (metabolism)