Back to Search
Start Over
Impaired non-canonical transforming growth factor-β signalling prevents profibrotic phenotypes in cultured peptidylarginine deiminase 4-deficient murine cardiac fibroblasts.
- Source :
- Journal of Cellular & Molecular Medicine; Oct2021, Vol. 25 Issue 20, p9674-9684, 11p
- Publication Year :
- 2021
-
Abstract
- Transforming growth factor-ß (TGF-ß) becomes rapidly activated in the infarcted heart. Hence, TGF-ß-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-ß 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-ß- stimulated WT CFs. Although the SMAD-dependent TGF-ß pathway was not disturbed in PAD4-/- CFs, TGF-ß 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-3ß (GSK-3ß). Consequently, PAD4-/- CFs did not upregulate collagen I and a-smooth muscle actin (a-SMA) expression after TGF-ß treatment. Thus, PAD4 is substantially involved in the regulation of non-canonical TGF-ß signalling and may represent a therapeutic target for the treatment of adverse cardiac remodelling. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15821838
- Volume :
- 25
- Issue :
- 20
- Database :
- Complementary Index
- Journal :
- Journal of Cellular & Molecular Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 153523904
- Full Text :
- https://doi.org/10.1111/jcmm.16915