Parichatikanond W.Duangrat R.Mangmool S.Mahidol University2023-06-012023-06-012023-07-15European Journal of Pharmacology Vol.951 (2023)00142999https://repository.li.mahidol.ac.th/handle/20.500.14594/82896Angiotensin 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.Pharmacology, Toxicology and PharmaceuticsArticleSCOPUS10.1016/j.ejphar.2023.1757802-s2.0-851598087701879071237209939