Paper of the Month

September 2019


TIP30 counteracts cardiac hypertrophy and failure by inhibiting translational elongation. EMBO Mol Med. DZHK authors: A. Grund, M. Malek Mohammadi, F. A. Trogisch, E. Riechert, M. Völkers, S. Doroudgar, A. Jungmann, H. A. Katus, O. J. Müller, J. Heineke

The mammalian adult heart expands in size mainly as a result of cardiac muscle cell growth due to enhanced protein synthesis. During common human diseases such as chronic arterial hypertension, aortic valve stenosis, but also inherited cardiomyopathies, exaggerated heart growth is associated with the development of heart failure and poor prognosis. Cardiac hypertrophy, however, is not sufficiently addressed by current treatment strategies. For this study, it was hypothesized that endogenous negative regulators of protein synthesis exist in the heart to prevent aggravated hypertrophy and that these regulators could potentially be used for therapeutic purposes in the future.
A team of international investigators led by Dr. Andrea Grund and Prof. Dr. Jörg Heineke from the Medical Faculty Mannheim of Heidelberg University has now found that the tumor suppressor gene TIP30 counteracts cardiomyocyte growth by binding to the elongation factor 1A (eEF1A). eEF1A is known to promote translation by delivering amino acids to the ribosomes. The new findings suggest that TIP30 through binding to eEF1A reduces protein synthesis by interfering with the interaction between eEF1A and its guanine nucleotide exchange factor eEF1B2, which keeps eEF1A in its active state. Due to this mechanism, even only a reduction of TIP30 by around 50% in heterozygous TIP30 knock-out mice led to increased cardiac protein synthesis, hypertrophy and cardiac dysfunction in response to pathological pressure overload.     

TIP30 overexpression by adeno-associated viruses, in turn, led to a sustained improvement of cardiac function and inhibited myocardial protein synthesis as well as hypertrophy during pressure overload. Importantly, TIP30 levels in relation to its target eEF1A are markedly downregulated in failing and cardiomyopathic human hearts, which according to this study´s findings leave eEF1A active and thereby promotes cardiac hypertrophy and failure. Indeed, the phenotype of heterozygous TIP30 knock-out mice during pressure overload could be significantly ameliorated by inhibiting eEF1A with the substance Narciclasine. On the other hand, overexpression of TIP30 in cardiomyopathic mice with endogenous TIP30 downregulation potently reduced hypertrophic heart growth over time. Therefore, it was demonstrated that exaggerated translational elongation is maladaptive during pathological overload and cardiomyopathy. In this regard, reduced TIP30 levels and more active eEF1A in failing hearts might be an interesting new therapeutic target, which could be addressed for example by TIP30 overexpression or eEF1A inhibition through substances like Narciclasine.

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