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Int J Cardiol. 2013 Sep 30;168(2):1447-52. doi: 10.1016/j.ijcard.2012.12.094. Epub 2013 Jan 27.

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

Author information

1
Center for Cardiovascular Research, Charité Medical School, Berlin, Germany; Applied Cachexia Research, Department of Cardiology, Charité Medical School, Berlin, Germany.

Abstract

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.

KEYWORDS:

Cardiomyopathy; DCM; TWIST1; Ubiquitin proteasome system; microRNA

PMID:
23360823
DOI:
10.1016/j.ijcard.2012.12.094
[Indexed for MEDLINE]
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