Sustained AT1R stimulation induces upregulation of growth factors in human cardiac fibroblasts via Gαq/TGF-β/ERK signaling that influences myocyte hypertrophy

Duangrat, Ratchanee; Parichatikanond, Warisara; Morales, Noppawan Phumala; Pinthong, Darawan; Mangmool, Supachoke

doi:10.1016/j.ejphar.2022.175384

Cited by 13 publications

(11 citation statements)

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“…TGF-β1 and ET-1 are downstream effectors of Ang II and have been associated with ATR signaling. In rat aorta, Ang II induced the upregulation of TGF-β1 [ 11 ] and ET-1 protein expression [ 20 ]. Next, we used LY2109761 (TβRI/II inhibitor) and bosentan (ETR antagonist; ERA) to investigate the contributions of TGF-β1 and ET-1 to Ang II-induced myofibroblast differentiation.…”

Section: Resultsmentioning

confidence: 99%

“…AT 1 R stimulation leads to G protein coupling and dissociation of G α q protein from G βγ subunit [ 10 ]. Our previous study demonstrated that AT 1 R mediated upregulation of growth factors through G αq protein, not G αi or G α12/13 proteins [ 11 ]. In addition, G βγ subunit of ATRs is also known to regulate the activities of targeted proteins.…”

Section: Discussionmentioning

confidence: 99%

“…In TGF-β1 deficient mice, administration of Ang II did not promote myocardial fibrosis and hypertrophy [ 37 ]. Moreover, Ang II induced TGF-β1 expression in cardiac myocytes and fibroblasts, and upregulation of TGF-β1 was required for Ang II-induced hypertrophy [ 11 , 12 ]. In line with previous studies, blockade of TGF-β signaling with LY2109761 (TβRI/II inhibitor) significantly inhibited Ang II-induced myofibroblast differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Ang II-induced collagen synthesis required TGF-β/Smad and MAPK signaling [ 39 ]. In addition, activation of ERK1/2 by Ang II is dependent on TGF-β [ 11 ]. The findings from our study demonstrated that inhibition of either Smad3 or ERK1/2 activities attenuate TGF-β1-stimulated myofibroblast differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Transforming growth factor-beta1 (TGF-β1), a potent profibrotic mediator, has been implicated in ATR signaling. Stimulation of AT 1 Rs induced TGF-β1 synthesis and secretion in cardiac fibroblasts, and upregulation of TGF-β1 is necessary for Ang II-mediated hypertrophy and fibrosis [ 11 , 12 ]. The canonical Smads and non-canonical mitogen-activated protein kinase (MAPK) proteins are the major downstream effectors of the Ang II/TGF-β1 signaling cascade in the cardiovascular system [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Dual Blockade of TGF-β Receptor and Endothelin Receptor Synergistically Inhibits Angiotensin II-Induced Myofibroblast Differentiation: Role of AT1R/Gαq-Mediated TGF-β1 and ET-1 Signaling

Duangrat

Parichatikanond

Mangmool

2023

IJMS

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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 AT1R/Gαq axis in adult human cardiac fibroblasts (HCFs). Following AT1R stimulation, Gαq protein, not Gβγ 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 AT1R/Gαq 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 (ETAR), 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 AT1R/Gαq 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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%