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- W3201351106 abstract "Abstract Transforming growth factor‐β (TGF‐β) becomes rapidly activated in the infarcted heart. Hence, TGF‐β‐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‐β 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‐β‐stimulated WT CFs. Although the SMAD‐dependent TGF‐β pathway was not disturbed in PAD4 ‐/‐ CFs, TGF‐β 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‐3β (GSK‐3β). Consequently, PAD4 ‐/‐ CFs did not upregulate collagen I and α‐smooth muscle actin (α‐SMA) expression after TGF‐β treatment. Thus, PAD4 is substantially involved in the regulation of non‐canonical TGF‐β signalling and may represent a therapeutic target for the treatment of adverse cardiac remodelling." @default.
- W3201351106 created "2021-09-27" @default.
- W3201351106 creator A5036577238 @default.
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- W3201351106 date "2021-09-14" @default.
- W3201351106 modified "2023-10-01" @default.
- W3201351106 title "Impaired non‐canonical transforming growth factor‐β signalling prevents profibrotic phenotypes in cultured peptidylarginine deiminase 4‐deficient murine cardiac fibroblasts" @default.
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- W3201351106 doi "https://doi.org/10.1111/jcmm.16915" @default.
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