Endothelin-1 Induces Cell Proliferation and Myofibroblast Differentiation through the ET<inf>A</inf>R/G<inf>αq</inf>/ERK Signaling Pathway in Human Cardiac Fibroblasts
Issued Date
2023-03-01
Resource Type
ISSN
16616596
eISSN
14220067
Scopus ID
2-s2.0-85149874441
Pubmed ID
36901906
Journal Title
International Journal of Molecular Sciences
Volume
24
Issue
5
Rights Holder(s)
SCOPUS
Bibliographic Citation
International Journal of Molecular Sciences Vol.24 No.5 (2023)
Suggested Citation
Duangrat R., Parichatikanond W., Likitnukul S., Mangmool S. Endothelin-1 Induces Cell Proliferation and Myofibroblast Differentiation through the ET<inf>A</inf>R/G<inf>αq</inf>/ERK Signaling Pathway in Human Cardiac Fibroblasts. International Journal of Molecular Sciences Vol.24 No.5 (2023). doi:10.3390/ijms24054475 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/81634
Title
Endothelin-1 Induces Cell Proliferation and Myofibroblast Differentiation through the ET<inf>A</inf>R/G<inf>αq</inf>/ERK Signaling Pathway in Human Cardiac Fibroblasts
Author's Affiliation
Other Contributor(s)
Abstract
Endothelin-1 (ET-1) has been implicated in the pathogenesis of cardiac fibrosis. Stimulation of endothelin receptors (ETR) with ET-1 leads to fibroblast activation and myofibroblast differentiation, which is mainly characterized by an overexpression of α-smooth muscle actin (α-SMA) and collagens. Although ET-1 is a potent profibrotic mediator, the signal transductions and subtype specificity of ETR contributing to cell proliferation, as well as α-SMA and collagen I synthesis in human cardiac fibroblasts are not well clarified. This study aimed to evaluate the subtype specificity and signal transduction of ETR on fibroblast activation and myofibroblast differentiation. Treatment with ET-1 induced fibroblast proliferation, and synthesis of myofibroblast markers, α-SMA, and collagen I through the ETAR subtype. Inhibition of Gαq protein, not Gαi or Gβγ, inhibited these effects of ET-1, indicating the essential role of Gαq protein-mediated ETAR signaling. In addition, ERK1/2 was required for ETAR/Gαq axis-induced proliferative capacity and overexpression of these myofibroblast markers. Antagonism of ETR with ETR antagonists (ERAs), ambrisentan and bosentan, inhibited ET-1-induced cell proliferation and synthesis of α-SMA and collagen I. Furthermore, ambrisentan and bosentan promoted the reversal of myofibroblasts after day 3 of treatment, with loss of proliferative ability and a reduction in α-SMA synthesis, confirming the restorative effects of ERAs. This novel work reports on the ETAR/Gαq/ERK signaling pathway for ET-1 actions and blockade of ETR signaling with ERAs, representing a promising therapeutic strategy for prevention and restoration of ET-1-induced cardiac fibrosis.