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TIP30 counteracts cardiac hypertrophy and failure by inhibiting translational elongation

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Item Type:Article
Title:TIP30 counteracts cardiac hypertrophy and failure by inhibiting translational elongation
Creators Name:Grund, A. and Szaroszyk, M. and Korf-Klingebiel, M. and Malek Mohammadi, M. and Trogisch, F.A. and Schrameck, U. and Gigina, A. and Tiedje, C. and Gaestel, M. and Kraft, T. and Hegermann, J. and Batkai, S. and Thum, T. and Perrot, A. and Remedios, C.D. and Riechert, E. and Völkers, M. and Doroudgar, S. and Jungmann, A. and Bauer, R. and Yin, X. and Mayr, M. and Wollert, K.C. and Pich, A. and Xiao, H. and Katus, H.A. and Bauersachs, J. and Müller, O.J. and Heineke, J.
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.
Keywords:Cardiac Hypertrophy, Cardiomyopathy, Heart Failure, Protein Synthesis, Translational Elongation, Animals, Mice
Source:EMBO Molecular Medicine
Page Range:e10018
Date:1 October 2019
Official Publication:https://doi.org/10.15252/emmm.201810018
PubMed:View item in PubMed

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