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TWIST1 regulates the activity of ubiquitin proteasome system via the miR-199/124 cluster in human end-stage dilated cardiomyopathy.
MedLine Citation:
PMID:  23360823     Owner:  NLM     Status:  Publisher    
BACKGROUND: The transcription factor TWIST1 has been described to regulate the microRNA (miR)-199/214 cluster. Genetic disruption of TWIST1 resulted in a cachectic phenotype and early death of the knock-out mice. This might be connected to the activity of the ubiquitin-proteasome-system (UPS), as miR-199a has been suggested to regulate the ubiquitin E2 ligases Ube2i and Ube2g1. METHODS: Cardiac tissue from explanted hearts of 42 patients with dilated cardiomyopathy and 20 healthy donor hearts were analysed for protein expression of TWIST1 and its inhibitors Id-1, MuRF-1 and MAFbx, the expression of miR-199a, -199b and -214, as well as the activity of the UPS by using specific fluorogenic substrates. RESULTS: TWIST1 was repressed in patients with dilated cardiomyopathy by 43% (p=0.003), while Id1 expression was unchanged. This was paralleled by a reduced expression of miR-199a by 38±9% (p=0.053), miR-199b by 36±13% (p=0.019) and miR-214 by 41±11% (p=0.0158) compared to donor hearts. An increased peptidylglutamyl-peptide-hydrolysing activity (p<0.0001) was observed in the UPS, while the chymotrypsin-like and trypsin-like activities were unchanged (both p>0.2). The protein levels of the rate limiting ubiquitin E3-ligases MuRF-1 and MAFbx were up-regulated (p=0.006 and 0.038, respectively). Mechanistically silencing of TWIST1 using siRNA in primary rat cardiomyocytes led to a down-regulation of the miR-199/214 cluster and to a subsequent up-regulation of Ube2i. CONCLUSION: The TWIST1/miR-199/214 axis is down-regulated in dilated cardiomyopathy, which is likely to play a role in the increased activity of the UPS. This may contribute to the loss of cardiac mass during dilatation of the heart.
Anna Baumgarten; Claudia Bang; Anika Tschirner; Anke Engelmann; Volker Adams; Stephan von Haehling; Wolfram Doehner; Reinhard Pregla; Markus Anker; Kinga Blecharz; Rudolf Meyer; Roland Hetzer; Stefan D Anker; Thomas Thum; Jochen Springer
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-26
Journal Detail:
Title:  International journal of cardiology     Volume:  -     ISSN:  1874-1754     ISO Abbreviation:  Int. J. Cardiol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-30     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8200291     Medline TA:  Int J Cardiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2013. Published by Elsevier Ireland Ltd.
Center for Cardiovascular Research, Charité Medical School, Berlin, Germany; Applied Cachexia Research, Department of Cardiology, Charité Medical School, Berlin, Germany.
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