Open AccessTIP 30 counteracts cardiac hypertrophy and failure by inhibiting translational elongation
Author(s) -
Grund Andrea,
Szaroszyk Malgorzata,
KorfKlingebiel Mortimer,
Malek Mohammadi Mona,
Trogisch Felix A,
Schrameck Ulrike,
Gigina Anna,
Tiedje Christopher,
Gaestel Matthias,
Kraft Theresia,
Hegermann Jan,
Batkai Sandor,
Thum Thomas,
Perrot Andreas,
Remedios Cris dos,
Riechert Eva,
Völkers Mirko,
Doroudgar Shirin,
Jungmann Andreas,
Bauer Ralf,
Yin Xiaoke,
Mayr Manuel,
Wollert Kai C,
Pich Andreas,
Xiao Hua,
Katus Hugo A,
Bauersachs Johann,
Müller Oliver J,
Heineke Joerg
Publication year - 2019
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201810018
Subject(s) - pressure overload , muscle hypertrophy , heart failure , elongation factor , medicine , hypertrophic cardiomyopathy , cardiac function curve , cardiomyopathy , cardiac hypertrophy , cardiology , microbiology and biotechnology , chemistry , endocrinology , biology , biochemistry , rna , ribosome , gene
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 TIP 30 as novel inhibitor of cardiac hypertrophy and dysfunction. Reduced TIP 30 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 TIP 30 levels in samples from patients suffering from end‐stage heart failure or hypertrophic cardiomyopathy. Importantly, therapeutic overexpression of TIP 30 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 TIP 30 binds the eukaryotic elongation factor 1A ( eEF 1A) to prevent the interaction with its essential co‐factor eEF 1B2 and translational elongation. Therefore, TIP 30 could be a therapeutic target to counteract cardiac hypertrophy.