GDF15 Promotes Cardiac Fibrosis and Proliferation of Cardiac Fibroblasts via the MAPK/ERK1/2 Pathway after Irradiation in Rats

Guo, Huan; Zhao, Xinke; Li, Haining; Liu, Kedan; Jiang, Hugang; Zeng, Xu; Chang, Juan; Ma, Chengxu; Fu, Zhaoyuan; Lv, Xinfang; Wang, Tao; Guo, Hongyun; Li, Kai; Su, Hongling; Li, Yingdong

doi:10.1667/rade-20-00206.1

Cited by 14 publications

(6 citation statements)

References 24 publications

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“…In addition, decreased growth and activation of lung fibroblasts due to GDF15-associated alterations in the TGF-Smad pathway have been described [ 59 ]. Contrarily, Guo et al recently revealed that GDF15 can promote proliferation in newborn rat cardiac fibroblasts after irradiation, which was confirmed by the increased cell proliferation rate and increased expression of fibrosis markers (Col1α and αSma) after transfection with GDF15 in vitro [ 60 ]. However, our data support an antiproliferative effect of GDF15, specifically on hPdLFs, in terms of decreased Ki67, whereas we could not detect an impact on the apoptosis rate of hPdLFs.…”

Section: Discussionmentioning

confidence: 99%

GDF15 Promotes the Osteogenic Cell Fate of Periodontal Ligament Fibroblasts, thus Affecting Their Mechanobiological Response

Lösch,

Stemmler,

Fischer

et al. 2023

IJMS

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Periodontal ligament fibroblasts (PdLFs) exert important functions in oral tissue and bone remodeling following mechanical forces, which are specifically applied during orthodontic tooth movement (OTM). Located between the teeth and the alveolar bone, mechanical stress activates the mechanomodulatory functions of PdLFs including regulating local inflammation and activating further bone-remodeling cells. Previous studies suggested growth differentiation factor 15 (GDF15) as an important pro-inflammatory regulator during the PdLF mechanoresponse. GDF15 exerts its effects through both intracrine signaling and receptor binding, possibly even in an autocrine manner. The extent to which PdLFs are susceptible to extracellular GDF15 has not yet been investigated. Thus, our study aims to examine the influence of GDF15 exposure on the cellular properties of PdLFs and their mechanoresponse, which seems particularly relevant regarding disease- and aging-associated elevated GDF15 serum levels. Therefore, in addition to investigating potential GDF15 receptors, we analyzed its impact on the proliferation, survival, senescence, and differentiation of human PdLFs, demonstrating a pro-osteogenic effect upon long-term stimulation. Furthermore, we observed altered force-related inflammation and impaired osteoclast differentiation. Overall, our data suggest a major impact of extracellular GDF15 on PdLF differentiation and their mechanoresponse.

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Section: Discussionmentioning

confidence: 99%

GDF15 Promotes the Osteogenic Cell Fate of Periodontal Ligament Fibroblasts, thus Affecting Their Mechanobiological Response

Lösch,

Stemmler,

Fischer

et al. 2023

IJMS

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show abstract

“…Among them, mediators related to cardiac fibrosis include transforming growth factor- β (TGF- β ) and platelet-derived growth factor [ 7 ]. Although more and more researchers have made great efforts to slow the progression of cardiac fibrosis, the molecular mechanism has not been clarified yet [ 8 ]. Further exploration and research on the containment of cardiac fibrosis are of great significance for the cognition, prevention, and treatment of cardiac fibrosis-related diseases.…”

Section: Introductionmentioning

confidence: 99%

lncRNA Vgll3 Regulates the Activated Proliferation of Mouse Myocardial Fibroblasts through TGF-β3-Related Pathway

Liu

Chen

Meng

2022

BioMed Research International

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Background. Cardiac fibrosis is a risk factor leading to various cardiac diseases, and its mechanism has not been clarified. However, long noncoding RNA (lncRNA) can mediate the pathological process of cardiac fibrosis. Objective. This study is aimed at determining the pathological role of lncRNA Vgll3 in cardiac fibrosis and explore its potential mechanism. Methods. Myocardium fibroblasts (CFs) were isolated from mice and stimulated with angiotensin II (Ang-II). The expression of Vgll3 and transforming growth factor-β3 (TGF-β3) were detected by real-time fluorescence quantitative PCR (qPCR). Double luciferase reporter gene and western blot analysis (WB) were used to detect the effect of Vgll3 on TGF-β3 expression. The qPCR and WB were used to detect TGF-β3 pathway markers such as TGF-β3 and SMAD4, as well as cardiac fibrosis markers such as α-smooth muscle actin (α-SMA), fibronectin (Fn), and type I collagen (Col1). The proliferation of CFs in mice was analyzed by Cell Counting Kit-8 (CCK8) and 5-bromo-2-deoxyuracil (EdU) method. Results. Upregulation of Vgll3 promoted the expression of TGF-β3 and its downstream molecules in mouse CFs, while silencing of Vgll3 inhibited the TGF-β3 pathway. Upregulation of Vgll3 significantly promoted the activation and proliferation of mouse CFs cells. It promoted the mRNA and protein levels of α-SMA, Fn, Col1, and Col3, while silencing the expression of Vgll3 had the opposite effect. The above effects of upregulation of Vgll3 were counteracted by TGF-β3 knockdown intervention. Conclusion. Vgll3 can promote the activation and proliferation of CFs in mice by activating TGF-β3-related pathway.

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“…The expressions of α‐SMA (also known as a marker for activated VICs 25 ) and connective tissue growth factor (CTGF; involved in valvular fibrosis 26 ) were significantly upregulated in DKO valves at 2 months old (Figure 7B and 7C ). Additionally, growth differentiation factor‐15 (Gdf15), which belongs to the TGF‐β superfamily and has recently been shown to increase in cardiac fibrosis, 27 was increased in the DKO valves (Figure 7D ). These results indicate that Fbln4 deficiency in ECs may induce EndMT to generate activated VICs and cause valvular thickening and fibrosis, which subsequently promotes TAAs.…”

Section: Resultsmentioning

confidence: 98%

Protective Role of Endothelial Fibulin‐4 in Valvulo‐Arterial Integrity

Nguyen

Lino

Hang

et al. 2023

JAHA

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Background Homeostasis of the vessel wall is cooperatively maintained by endothelial cells (ECs), smooth muscle cells, and adventitial fibroblasts. The genetic deletion of fibulin‐4 ( Fbln4 ) in smooth muscle cells ( SMKO ) leads to the formation of thoracic aortic aneurysms with the disruption of elastic fibers. Although Fbln4 is expressed in the entire vessel wall, its function in ECs and relevance to the maintenance of valvulo‐arterial integrity are not fully understood. Methods and Results Gene silencing of FBLN4 was conducted on human aortic ECs to evaluate morphological changes and gene expression profile. Fbln4 double knockout ( DKO ) mice in ECs and smooth muscle cells were generated and subjected to histological analysis, echocardiography, Western blotting, RNA sequencing, and immunostaining. An evaluation of the thoracic aortic aneurysm phenotype and screening of altered signaling pathways were performed. Knockdown of FBLN4 in human aortic ECs induced mesenchymal cell–like changes with the upregulation of mesenchymal genes, including TAGLN and MYL9 . DKO mice showed the exacerbation of thoracic aortic aneurysms when compared with those of SMKO and upregulated Thbs1, a mechanical stress–responsive molecule, throughout the aorta. DKO mice also showed progressive aortic valve thickening with collagen deposition from postnatal day 14, as well as turbulent flow in the ascending aorta. Furthermore, RNA sequencing and immunostaining of the aortic valve revealed the upregulation of genes involved in endothelial‐to‐mesenchymal transition, inflammatory response, and tissue fibrosis in DKO valves and the presence of activated valve interstitial cells. Conclusions The current study uncovers the pivotal role of endothelial fibulin‐4 in the maintenance of valvulo‐arterial integrity, which influences thoracic aortic aneurysm progression.

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GDF15 Promotes Cardiac Fibrosis and Proliferation of Cardiac Fibroblasts via the MAPK/ERK1/2 Pathway after Irradiation in Rats

Cited by 14 publications

References 24 publications

GDF15 Promotes the Osteogenic Cell Fate of Periodontal Ligament Fibroblasts, thus Affecting Their Mechanobiological Response

GDF15 Promotes the Osteogenic Cell Fate of Periodontal Ligament Fibroblasts, thus Affecting Their Mechanobiological Response

lncRNA Vgll3 Regulates the Activated Proliferation of Mouse Myocardial Fibroblasts through TGF-β3-Related Pathway

Protective Role of Endothelial Fibulin‐4 in Valvulo‐Arterial Integrity

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