Universität zu Köln

Akboua, Hanane, Eghbalzadeh, Kaveh, Keser, Ugur, Wahlers, Thorsten and Paunel-Gorgulu, Adnana (2021). Impaired non-canonical transforming growth factor-beta signalling prevents profibrotic phenotypes in cultured peptidylarginine deiminase 4-deficient murine cardiac fibroblasts. J. Cell. Mol. Med., 25 (20). S. 9674 - 9685. HOBOKEN: WILEY. ISSN 1582-4934

Full text not available from this repository.

Abstract

Transforming growth factor-beta (TGF-beta) becomes rapidly activated in the infarcted heart. Hence, TGF-beta-mediated persistent activation of cardiac fibroblasts (CFs) and exaggerated fibrotic responses may result in adverse cardiac remodelling and heart failure. Additionally, peptidylarginine deiminase 4 (PAD4) was described to be implicated in organ fibrosis. Here, we investigated the impact of PAD4 on CF function and myofibroblast transdifferentiation in vitro. The expression of fibrosis-related genes was largely similar in cultured WT and PAD4(-/-) CFs of passage 3, although collagen III was reduced in PAD4(-/-) CFs. Exposure to TGF-beta inhibited proliferation and increased contractile activity and migration of WT CFs, but not of PAD4(-/-) CFs. However, under baseline conditions, PAD4(-/-) CFs showed comparable functional characteristics as TGF-beta-stimulated WT CFs. Although the SMAD-dependent TGF-beta pathway was not disturbed in PAD4(-/-) CFs, TGF-beta failed to activate protein kinase B (Akt) and signal transducer and activator of transcription 3 (STAT3) in these cells. Similar results were obtained in WT CFs treated with the PAD4 inhibitor Cl-amidine. Abrogated Akt activation was associated with diminished levels of phosphorylated, inactive glycogen synthase kinase-3 beta (GSK-3 beta). Consequently, PAD4(-/-) CFs did not upregulate collagen I and alpha-smooth muscle actin (alpha-SMA) expression after TGF-beta treatment. Thus, PAD4 is substantially involved in the regulation of non-canonical TGF-beta signalling and may represent a therapeutic target for the treatment of adverse cardiac remodelling.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Akboua, Hanane UNSPECIFIED UNSPECIFIED UNSPECIFIED Eghbalzadeh, Kaveh UNSPECIFIED UNSPECIFIED UNSPECIFIED Keser, Ugur UNSPECIFIED UNSPECIFIED UNSPECIFIED Wahlers, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Paunel-Gorgulu, Adnana UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-564821
DOI:	10.1111/jcmm.16915
Journal or Publication Title:	J. Cell. Mol. Med.
Volume:	25
Number:	20
Page Range:	S. 9674 - 9685
Date:	2021
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1582-4934
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NEUTROPHIL EXTRACELLULAR TRAPS; MATRIX METALLOPROTEINASES; CITRULLINATION; FIBROSIS; INHIBITION; ACTIVATION; EXPRESSION; PROTEINS; MUSCLE; MOUSE Multiple languages Cell Biology; Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/56482