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Dual Blockade of TGF-β Receptor and Endothelin Receptor Synergistically Inhibits Angiotensin II-Induced Myofibroblast Differentiation: Role of AT(1)R/G(αq)-Mediated TGF-β1 and ET-1 Signaling
Angiotensin II (Ang II) upregulates transforming growth factor-beta1 (TGF-β1) and endothelin-1 (ET-1) in various types of cells, and all of them act as profibrotic mediators. However, the signal transduction of angiotensin II receptor (ATR) for upregulation of TGF-β1 and ET-1, and their effectors th...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10138810/ https://www.ncbi.nlm.nih.gov/pubmed/37108136 http://dx.doi.org/10.3390/ijms24086972 |
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author | Duangrat, Ratchanee Parichatikanond, Warisara Mangmool, Supachoke |
author_facet | Duangrat, Ratchanee Parichatikanond, Warisara Mangmool, Supachoke |
author_sort | Duangrat, Ratchanee |
collection | PubMed |
description | Angiotensin II (Ang II) upregulates transforming growth factor-beta1 (TGF-β1) and endothelin-1 (ET-1) in various types of cells, and all of them act as profibrotic mediators. However, the signal transduction of angiotensin II receptor (ATR) for upregulation of TGF-β1 and ET-1, and their effectors that play an essential role in myofibroblast differentiation, are not fully understood. Therefore, we investigated the ATR networking with TGF-β1 and ET-1 and identified the signal transduction of these mediators by measuring the mRNA expression of alpha-smooth muscle actin (α-SMA) and collagen I using qRT-PCR. Myofibroblast phenotypes were monitored by α-SMA and stress fiber formation with fluorescence microscopy. Our findings suggested that Ang II induced collagen I and α-SMA synthesis and stress fiber formation through the AT(1)R/G(αq) axis in adult human cardiac fibroblasts (HCFs). Following AT(1)R stimulation, G(αq) protein, not G(βγ) subunit, was required for upregulation of TGF-β1 and ET-1. Moreover, dual inhibition of TGF-β and ET-1 signaling completely inhibited Ang II-induced myofibroblast differentiation. The AT(1)R/G(αq) cascade transduced signals to TGF-β1, which in turn upregulated ET-1 via the Smad- and ERK1/2-dependent pathways. ET-1 consecutively bound to and activated endothelin receptor type A (ET(A)R), leading to increases in collagen I and α-SMA synthesis and stress fiber formation. Remarkably, dual blockade of TGF-β receptor and ETR exhibited the restorative effects to reverse the myofibroblast phenotype induced by Ang II. Collectively, TGF-β1 and ET-1 are major effectors of AT(1)R/G(αq) cascade, and therefore, negative regulation of TGF-β and ET-1 signaling represents a targeted therapeutic strategy for the prevention and restoration of cardiac fibrosis. |
format | Online Article Text |
id | pubmed-10138810 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-101388102023-04-28 Dual Blockade of TGF-β Receptor and Endothelin Receptor Synergistically Inhibits Angiotensin II-Induced Myofibroblast Differentiation: Role of AT(1)R/G(αq)-Mediated TGF-β1 and ET-1 Signaling Duangrat, Ratchanee Parichatikanond, Warisara Mangmool, Supachoke Int J Mol Sci Article Angiotensin II (Ang II) upregulates transforming growth factor-beta1 (TGF-β1) and endothelin-1 (ET-1) in various types of cells, and all of them act as profibrotic mediators. However, the signal transduction of angiotensin II receptor (ATR) for upregulation of TGF-β1 and ET-1, and their effectors that play an essential role in myofibroblast differentiation, are not fully understood. Therefore, we investigated the ATR networking with TGF-β1 and ET-1 and identified the signal transduction of these mediators by measuring the mRNA expression of alpha-smooth muscle actin (α-SMA) and collagen I using qRT-PCR. Myofibroblast phenotypes were monitored by α-SMA and stress fiber formation with fluorescence microscopy. Our findings suggested that Ang II induced collagen I and α-SMA synthesis and stress fiber formation through the AT(1)R/G(αq) axis in adult human cardiac fibroblasts (HCFs). Following AT(1)R stimulation, G(αq) protein, not G(βγ) subunit, was required for upregulation of TGF-β1 and ET-1. Moreover, dual inhibition of TGF-β and ET-1 signaling completely inhibited Ang II-induced myofibroblast differentiation. The AT(1)R/G(αq) cascade transduced signals to TGF-β1, which in turn upregulated ET-1 via the Smad- and ERK1/2-dependent pathways. ET-1 consecutively bound to and activated endothelin receptor type A (ET(A)R), leading to increases in collagen I and α-SMA synthesis and stress fiber formation. Remarkably, dual blockade of TGF-β receptor and ETR exhibited the restorative effects to reverse the myofibroblast phenotype induced by Ang II. Collectively, TGF-β1 and ET-1 are major effectors of AT(1)R/G(αq) cascade, and therefore, negative regulation of TGF-β and ET-1 signaling represents a targeted therapeutic strategy for the prevention and restoration of cardiac fibrosis. MDPI 2023-04-09 /pmc/articles/PMC10138810/ /pubmed/37108136 http://dx.doi.org/10.3390/ijms24086972 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Duangrat, Ratchanee Parichatikanond, Warisara Mangmool, Supachoke Dual Blockade of TGF-β Receptor and Endothelin Receptor Synergistically Inhibits Angiotensin II-Induced Myofibroblast Differentiation: Role of AT(1)R/G(αq)-Mediated TGF-β1 and ET-1 Signaling |
title | Dual Blockade of TGF-β Receptor and Endothelin Receptor Synergistically Inhibits Angiotensin II-Induced Myofibroblast Differentiation: Role of AT(1)R/G(αq)-Mediated TGF-β1 and ET-1 Signaling |
title_full | Dual Blockade of TGF-β Receptor and Endothelin Receptor Synergistically Inhibits Angiotensin II-Induced Myofibroblast Differentiation: Role of AT(1)R/G(αq)-Mediated TGF-β1 and ET-1 Signaling |
title_fullStr | Dual Blockade of TGF-β Receptor and Endothelin Receptor Synergistically Inhibits Angiotensin II-Induced Myofibroblast Differentiation: Role of AT(1)R/G(αq)-Mediated TGF-β1 and ET-1 Signaling |
title_full_unstemmed | Dual Blockade of TGF-β Receptor and Endothelin Receptor Synergistically Inhibits Angiotensin II-Induced Myofibroblast Differentiation: Role of AT(1)R/G(αq)-Mediated TGF-β1 and ET-1 Signaling |
title_short | Dual Blockade of TGF-β Receptor and Endothelin Receptor Synergistically Inhibits Angiotensin II-Induced Myofibroblast Differentiation: Role of AT(1)R/G(αq)-Mediated TGF-β1 and ET-1 Signaling |
title_sort | dual blockade of tgf-β receptor and endothelin receptor synergistically inhibits angiotensin ii-induced myofibroblast differentiation: role of at(1)r/g(αq)-mediated tgf-β1 and et-1 signaling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10138810/ https://www.ncbi.nlm.nih.gov/pubmed/37108136 http://dx.doi.org/10.3390/ijms24086972 |
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