G<inf>αq</inf> protein-biased ligand of angiotensin II type 1 receptor mediates myofibroblast differentiation through TGF-β1/ERK axis in human cardiac fibroblasts
Issued Date
2023-07-15
Resource Type
ISSN
00142999
eISSN
18790712
Scopus ID
2-s2.0-85159808770
Pubmed ID
37209939
Journal Title
European Journal of Pharmacology
Volume
951
Rights Holder(s)
SCOPUS
Bibliographic Citation
European Journal of Pharmacology Vol.951 (2023)
Suggested Citation
Parichatikanond W., Duangrat R., Mangmool S. G<inf>αq</inf> protein-biased ligand of angiotensin II type 1 receptor mediates myofibroblast differentiation through TGF-β1/ERK axis in human cardiac fibroblasts. European Journal of Pharmacology Vol.951 (2023). doi:10.1016/j.ejphar.2023.175780 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/82896
Title
G<inf>αq</inf> protein-biased ligand of angiotensin II type 1 receptor mediates myofibroblast differentiation through TGF-β1/ERK axis in human cardiac fibroblasts
Author(s)
Author's Affiliation
Other Contributor(s)
Abstract
Angiotensin II receptors are members of G protein-coupled receptor superfamily that manifest biased signals toward G protein- and β-arrestin-dependent pathways. However, the role of angiotensin II receptor-biased ligands and the mechanisms underlying myofibroblast differentiation in human cardiac fibroblasts have not been fully elucidated. Our results demonstrated that antagonism of angiotensin II type 1 receptor (AT1 receptor) and blockade of Gαq protein suppressed angiotensin II (Ang II)-induced fibroblast proliferation, overexpression of collagen I and α-smooth muscle actin (α-SMA), and stress fibre formation, indicating the AT1 receptor/Gαq axis is necessary for fibrogenic effects of Ang II. Stimulation of AT1 receptors by their Gαq-biased ligand (TRV120055), but not β-arrestin-biased ligand (TRV120027), substantially exerted fibrogenic effects at a level similar to that of Ang II, suggesting that AT1 receptor induced cardiac fibrosis in a Gαq-dependent and β-arrestin-independent manner. Valsartan prevented TRV120055-mediated fibroblast activation. TRV120055 mediated the upregulation of transforming growth factor-beta1 (TGF-β1) through the AT1 receptor/Gαq cascade. In addition, Gαq protein and TGF-β1 were necessary for ERK1/2 activation induced by Ang II and TRV120055. Collectively, TGF-β1 and ERK1/2 are downstream effectors of the Gαq-biased ligand of AT1 receptor for the induction of cardiac fibrosis.