1. Academic Validation
  2. Gαq protein-biased ligand of angiotensin II type 1 receptor mediates myofibroblast differentiation through TGF-β1/ERK axis in human cardiac fibroblasts

Gαq protein-biased ligand of angiotensin II type 1 receptor mediates myofibroblast differentiation through TGF-β1/ERK axis in human cardiac fibroblasts

  • Eur J Pharmacol. 2023 May 18;175780. doi: 10.1016/j.ejphar.2023.175780.
Warisara Parichatikanond 1 Ratchanee Duangrat 2 Supachoke Mangmool 3
Affiliations

Affiliations

  • 1 Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, 10400, Thailand; Centre of Biopharmaceutical Science for Healthy Ageing (BSHA), Faculty of Pharmacy, Mahidol University, Bangkok, 10400, Thailand. Electronic address: [email protected].
  • 2 Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand; Molecular Medicine Graduate Program, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand. Electronic address: [email protected].
  • 3 Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand. Electronic address: [email protected].
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 prevents 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.

Keywords

AT(1) receptor; Biased ligand; Cardiac fibrosis; ERK1/2; G(αq) protein; TGF-β1; β-arrestin.

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