TIP 30 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.

Analysis of myocardial cellular gene expression during pressure overload reveals matrix based functional intercellular communication

“…TAC or sham surgery was performed by subjecting the aorta to a defined 26-gauge constriction in 8-9 weekold mice as described previously ( Appari et al., 2017 ; Grund et al., 2019 ) ( Heineke, 2013 ; Riehle and Bauersachs, 2019 ). Mice were subcutaneously (s.c.) injected with 0.02 mg/kg atropine and 0.1 mg/kg buprenorphine.…”

“…Anesthesia was maintained with 1-2% isoflurane via mask. Non-invasive echocardiography was performed in parasternal long- and short axis with a 30MHz transducer (Vevo 770, Visualsonics), as previously described ( Appari et al., 2017 ; Grund et al., 2019 ). LV end-diastolic diameter (LVEDD), enddiastolic average wall thickness (Wth), heart rate and enddiastolic volume (EDV) as well as endsystolic volume (ESV) were recorded or calculated.…”

Comprehensive Expression Analysis of Cardiac Fibroblast Growth Factor 23 in Health and Pressure-induced Cardiac Hypertrophy

“…Transverse aortic constriction (TAC) or sham surgery was performed in eight-week-old male and female Fgf23 fl/fl /cre − and Fgf23 fl/fl /cre + mice by subjecting the aorta to a defined constriction as previously described ( Grund et al, 2019a ). In brief, a 7–0 silk suture was tied around the aortic arch between the branches of the brachiocephalic trunk and the left common carotid artery and a blunted 27-gauge needle, after which the needle was removed to create a defined constriction.…”

Methylation of human elongation factor eEF1A2 is not essential for eEF1A2-eEF1B interaction

“…As the methylated Lys residues are localized on the surface of the eEF1A proteins one may suggest that this modification may influence the interaction of eEF1A with the protein partners. eEF1A has a number of confirmed translational [40,41] and nontranslational [7,8,[42][43][44] protein partners, thus the search for methylation-impacted protein-protein contacts is at the initial stage.…”