Pivotal Role of TGF-β/Smad Signaling in Cardiac Fibrosis: Non-coding RNAs as Effectual Players

Saadat, Somayeh; Noureddini, Mahdi; Mahjoubin‐Tehran, Maryam; Nazemi, Sina; Shojaie, Layla; Aschner, Michael; Maleki, Behnaz; Abbasi-Kolli, Mohammad; Moghadam, Hasan Rajabi; Alani, Behrang; Mirzaei, Hamed

doi:10.3389/fcvm.2020.588347

Cited by 97 publications

(69 citation statements)

References 169 publications

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“…Numerous studies have demonstrated that TGFβ/Bmp signaling is involved in cardiac remodeling and HF [ 16 – 18 ], and have been determined to be the most affected pathways in Gsα CMKO mice. Bmp10 , a peptide growth factor, belonging to the TGFβ superfamily [ 19 ], is a differentially expressed gene that was found, through RNA-seq analysis, to be downregulated >threefolds.…”

Section: Resultsmentioning

confidence: 99%

Gsα deficiency facilitates cardiac remodeling via CREB/ Bmp10-mediated signaling

Yin

Zhao

et al. 2021

Cell Death Discov.

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The stimulatory G-protein alpha subunit (Gsα), a ubiquitously expressed protein, mediates G-protein receptor-stimulated signal transduction. To investigate the functions of Gsα in cardiomyocytes. We developed transverse aortic constriction (TAC)-induced heart failure mouse models and tamoxifen-inducible transgenic mice with cardiac-specific Gsα disruption. We detected alterations in Gsα expression in TAC-induced heart failure mice. Moreover, we examined cardiac function and structure in mice with genetic Gsα deletion and investigated the underlying molecular mechanisms of Gsα function. We found that Gsα expression increased during the compensated cardiac hypertrophy period and decreased during the heart failure period. Moreover, cardiac-specific Gsα disruption deteriorated cardiac function and induced severe cardiac remodeling. Mechanistically, Gsα disruption decreased CREB1 expression and inhibited the Bmp10-mediated signaling pathway. In addition, we found that Gsα regulates Bmp10 expression through the binding of CREB1 to the Bmp10 promoter. Our results suggest that fluctuations in Gsα levels may play a vital role in the development of heart failure and that loss of Gsα function facilitates cardiac remodeling.

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Section: Resultsmentioning

confidence: 99%

Gsα deficiency facilitates cardiac remodeling via CREB/ Bmp10-mediated signaling

Yin

Zhao

et al. 2021

Cell Death Discov.

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“…Wu et al [ 26 ] demonstrated that miR-503 expression was decreased in TGF-β1 stimulated lung fibroblasts and upregulation of miR-503 attenuated CAF-like myofibroblastic phenotype in myofibroblasts. Several miRNAs are involved in cardiac fibrosis (reviewed in [ 27 ]), and another study has proposed that miR-503 modulates fibrosis by enhancing the ECM deposition in cardiac fibroblasts [ 28 ]. miR-708 is one of the more recently discovered miRNAs to play a role in fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Myofibroblast transdifferentiation is associated with changes in cellular and extracellular vesicle miRNA abundance

et al. 2021

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Transforming growth factor-beta 1 (TGF-β1), a pro-fibrotic tumour-derived factor promotes fibroblast differentiation in the tumour microenvironment and is thought to contribute to the development of pro-tumourigenic cancer-associated fibroblasts (CAFs) by promoting myofibroblast differentiation. miRNA dysregulation has been demonstrated in myofibroblast transdifferentiation and CAF activation, however, their expression varies among cell types and with the method of fibroblast induction. Here, the expression profile of miRNA in human primary oral fibroblasts treated with TGF-β1, to derive a myofibroblastic, CAF-like phenotype, was determined compared to untreated fibroblasts. Myofibroblast transdifferentiation was determined by the expression of alpha-smooth muscle actin (α-SMA) and fibronectin-1 extra domain A (FN-EDA1) using quantitative real-time PCR (qRT-PCR) and western blot. The formation of stress fibres was assessed by fluorescence microscopy, and associated changes in contractility were assessed using collagen contraction assays. Extracellular vesicles (EVs) were purified by using size exclusion chromatography and ultracentrifugation and their size and concentration were determined by nanoparticle tracking analysis. miRNA expression profiling in oral fibroblasts treated with TGF-β1 and their extracellular vesicles was carried out using tiling low-density array cards. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used to perform functional and pathway enrichment analysis of target genes. In this study, TGF-β1 induced a myofibroblastic phenotype in normal oral fibroblasts as assessed by expression of molecular markers, the formation of stress fibres and increased contractility. TaqMan Low-Density Array (TLDA) analysis demonstrated that miR-503 and miR-708 were significantly upregulated, while miR-1276 was significantly downregulated in TGF-β1-treated oral fibroblasts (henceforth termed experimentally-derived CAF, eCAF). The gene functional enrichment analysis showed that the candidate miRNAs have the potential to modulate various pathways; including the Ras associated protein 1 (Rap1), PI3K-Akt, and tumour necrosis factor (TNF) signalling pathways. In addition, altered levels of several miRNAs were detected in eCAF EV, including miR-142 and miR-222. No differences in size or abundance of EV were detected between eCAF and normal oral fibroblast (NOF). Little overlap was observed between changes in cellular and EV miRNA profiles, suggesting the possibility of selective loading of EV miRNA. The study reveals miRNA expression signature could be involved in myofibroblast transdifferentiation and the miRNA cargo of their EV, providing novel insight into the involvement of miRNA in CAF development and function.

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“…In addition, the expression of the main AngII receptors, including the pro-inflammatory, pro-hypertrophic, and pro-fibrotic AT1 receptor, and the anti-inflammatory, anti-hypertrophic and anti-fibrotic type 2 (AT2) receptor were studied at the protein level [ 14 , 15 ] ( Figure 6 a–f). AT1 receptor was described to activate TGF-β, which can induce fibrosis via the canonical SMAD-dependent and the non-canonical SMAD-independent signaling pathways [ 14 , 15 , 26 ].…”

Section: Resultsmentioning

confidence: 99%

Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease

Kovács

Varga

et al. 2021

IJMS

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Radiation-induced heart disease (RIHD) is a potential late side-effect of thoracic radiotherapy resulting in left ventricular hypertrophy (LVH) and fibrosis due to a complex pathomechanism leading to heart failure. Angiotensin-II receptor blockers (ARBs), including losartan, are frequently used to control heart failure of various etiologies. Preclinical evidence is lacking on the anti-remodeling effects of ARBs in RIHD, while the results of clinical studies are controversial. We aimed at investigating the effects of losartan in a rat model of RIHD. Male Sprague-Dawley rats were studied in three groups: (1) control, (2) radiotherapy (RT) only, (3) RT treated with losartan (per os 10 mg/kg/day), and were followed for 1, 3, or 15 weeks. At 15 weeks post-irradiation, losartan alleviated the echocardiographic and histological signs of LVH and fibrosis and reduced the overexpression of chymase, connective tissue growth factor, and transforming growth factor-beta in the myocardium measured by qPCR; likewise, the level of the SMAD2/3 protein determined by Western blot decreased. In both RT groups, the pro-survival phospho-AKT/AKT and the phospho-ERK1,2/ERK1,2 ratios were increased at week 15. The antiremodeling effects of losartan seem to be associated with the repression of chymase and several elements of the TGF-β/SMAD signaling pathway in our RIHD model.

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Pivotal Role of TGF-β/Smad Signaling in Cardiac Fibrosis: Non-coding RNAs as Effectual Players

Cited by 97 publications

References 169 publications

Gsα deficiency facilitates cardiac remodeling via CREB/ Bmp10-mediated signaling

Gsα deficiency facilitates cardiac remodeling via CREB/ Bmp10-mediated signaling

Myofibroblast transdifferentiation is associated with changes in cellular and extracellular vesicle miRNA abundance

Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease

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