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TWIST1 regulates the activity of ubiquitin proteasome system via the miR-199/214 cluster in human end-stage dilated cardiomyopathy.

Authors: Baumgarten, Anna  Bang, Claudia  Tschirner, Anika  Engelmann, Anke  Adams, Volker  von Haehling, Stephan  Doehner, Wolfram  Pregla, Reinhard  Anker, Markus S  Blecharz, Kinga  Meyer, Rudolf  Hetzer, Roland  Anker, Stefan D  Thum, Thomas  Springer, Jochen 
Citation: Baumgarten A, etal., Int J Cardiol. 2013 Sep 30;168(2):1447-52. doi: 10.1016/j.ijcard.2012.12.094. Epub 2013 Jan 27.
Pubmed: (View Article at PubMed) PMID:23360823
DOI: Full-text: DOI:10.1016/j.ijcard.2012.12.094


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. The protein levels of the rate limiting ubiquitin E3-ligases MuRF-1 and MAFbx were up-regulated (p=0.005 and p=0.0156, 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.

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CRRD Object Information
CRRD ID: 13831294
Created: 2018-12-20
Species: All species
Last Modified: 2018-12-20
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.