EOFAZ inhibits endothelial‑to‑mesenchymal transition through downregulation of KLF4

Zhang, Yanyan; Li, Chen; Huang, Yongpan; Zhao, Shuang; Xu, Yini; Chen, Yan; Jiang, Feng; Tao, Ling; Shen, Xiangchun

doi:10.3892/ijmm.2020.4572

Cited by 12 publications

(11 citation statements)

References 52 publications

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“…33 Although KLF4 is known to interact with TGF-β signaling to regulate endothelial-to-mesenchymal transition, it remains elusive whether and how KLF4 regulates the BMP/TGF-β signaling axes in ECs under health and disease conditions remain elusive. 35–38…”

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confidence: 99%

MED1 Regulates BMP/TGF-β in Endothelium: Implication for Pulmonary Hypertension

Wang

Yang

Jiao

et al. 2022

Circulation Research

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BACKGROUND: Dysregulated BMP (bone morphogenetic protein) or TGF-β (transforming growth factor beta) signaling pathways are imperative in idiopathic and familial pulmonary arterial hypertension (PAH) as well as experimental pulmonary hypertension (PH) in rodent models. MED1 (mediator 1) is a key transcriptional co-activator and KLF4 (Krüppel-like factor 4) is a master transcription factor in endothelium. However, MED1 and KLF4 epigenetic and transcriptional regulations of the BMP/TGF-β axes in pulmonary endothelium and their dysregulations leading to PAH remain elusive. We investigate the MED1/KLF4 co-regulation of the BMP/TGF-β axes in endothelium by studying the epigenetic regulation of BMPR2 (BMP receptor type II), ETS-related gene ( ERG ), and TGFBR2 (TGF-β receptor 2) and their involvement in the PH. METHODS: High-throughput screening involving data from RNA-seq, MED1 ChIP-seq, H3K27ac ChIP-seq, KLF4 ATAC-seq, and high-throughput chromosome conformation capture together with in silico computations were used to explore the epigenetic and transcriptional regulation of BMPR2, ERG, and TGFBR2 by MED1 and KLF4. In vitro experiments with cultured pulmonary arterial endothelial cells and bulk assays were used to validate results from these in silico analyses. Lung tissue from patients with idiopathic PAH, animals with experimental PH, and mice with endothelial ablation of MED1 (EC- MED1 −/− ) were used to study the PH-protective effect of MED1. RESULTS: Levels of MED1 were decreased in lung tissue or pulmonary arterial endothelial cells from idiopathic PAH patients and rodent PH models. Mechanistically, MED1 acted synergistically with KLF4 to transactivate BMPR2, ERG, and TGFBR2 via chromatin remodeling and enhancer-promoter interactions. EC- MED1 −/− mice showed PH susceptibility. In contrast, MED1 overexpression mitigated the PH phenotype in rodents. CONCLUSIONS: A homeostatic regulation of BMPR2, ERG, and TGFBR2 in ECs by MED1 synergistic with KLF4 is essential for the normal function of the pulmonary endothelium. Dysregulation of MED1 and the resulting impairment of the BMP/TGF-β signaling is implicated in the disease progression of PAH in humans and PH in rodent models.

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mentioning

confidence: 99%

MED1 Regulates BMP/TGF-β in Endothelium: Implication for Pulmonary Hypertension

Wang

Yang

Jiao

et al. 2022

Circulation Research

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“…This study analyzed the expression of the CAV-1 gene in fibrotic muscles of rats submitted to treatment with the VOAz. An in vitro study observed that the use of the VOAz inhibited the extension of EndMT induced by TGF-β1 (Zhang et al, 2020). A negative involvement of the TGF-β1 has been reported in L-type calcium channels in cardiac muscles and in fibrotic cardiac pathology (Lei et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Chemical characterization and effects of volatile oil of Alpinia zerumbet on the quality of collagen deposition and caveolin-1 expression in a muscular fibrosis murine model

et al. 2024

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This study evaluated the effect of the volatile oil of Alpinia zerumbet (VOAz) on caveolin-1 gene expression and muscular fibrosis. The rats were immobilized to induce fibrosis of the gastrocnemius muscle, and they were treated with VOAz. Collagen quality was assessed by histology and the expression of the caveolin-1 (CAV-1) gene was evaluated using qPCR. Histomorphological analysis indicated a significant reduction in the perimeter, width, and intensity of collagen in the treated groups, thus showing that the oil was effective in regulating the quality of collagen at the three concentrations. The results of expression levels suggested a decrease in the lesioned group and in two treatment groups (0.0115 µg/g and 0.009 µg/g). However, with the lowest concentration (0.0065 µg/g), no significant difference was observed, with levels similar to those found in healthy tissue. Therefore, the results showed that VOAz has the potential to be a non-invasive and low-cost alternative to aid in the treatment of muscular fibrosis.

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“…Accumulating evidence has suggested that eNOS/NO signaling axis was involved in vessel relaxation, vascular smooth muscle cell proliferation and ischemia/reperfusion injury ( 25 ). Moreover, our previous study revealed that KLF4 knockdown in endothelial cells could inhibit TGF-β-induced cell proliferation, migration and phenotypic changes, and effectively inhibited EndMT, suggesting that KLF4 may serve a role in EndMT ( 26 ). However, to the best of our knowledge, few studies have investigated the regulatory effect of the KLF4/eNOS signaling pathway in vascular damage-associated disorders.…”

Section: Discussionmentioning

confidence: 99%

Salidroside inhibits endothelial‑mesenchymal transition via the KLF4/eNOS signaling pathway

et al. 2021

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Homocysteine (Hcy) was discovered to be an independent risk factor for the development of atherosclerosis (AS). Moreover, endothelial-mesenchymal transition (EndMT) was found to be one of main mechanisms contributing to the pathogenesis of AS. Salidroside (SAL) has diverse pharmacological activities, including anti-inflammatory, anti-cancer, anti-oxidative and anti-fibrosis properties. However, whether SAL serves a beneficial role in Hcy-induced EndMT remains unknown. The present study aimed to investigate whether SAL exerted its effects on Hcy-induced EndMT via the Kruppel-like factor 4 (KLF4)/endothelial nitric oxide (NO) synthase (eNOS) signaling pathway. HUVECs were pretreated with high and low doses (10 or 50 µmol/l) of SAL for 2 h, followed by 1 mmol/l Hcy for 48 h to induce EndMT. Western blotting was used to analyze the protein expression levels of the endothelial marker, VE-cadherin, the mesenchymal cell marker, α-smooth muscle actin (SMA), and the nuclear transcription factors, KLF4 and eNOS. Wound healing assays were used to determine the cell migratory ability, and the levels of NO in the cell culture supernatants were measured using a nitrate reductase assay. Cellular immunofluorescence was used to analyze the expression and localization of KLF4. Small interfering (si)RNA targeting KLF4 (siKLF4) was used to knock down KLF4 expression in HUVECs. The results of the present study revealed that treatment with SAL upregulated the expression levels of VE-cadherin, downregulated the expression levels of α-SMA, reduced cell migration and activated the eNOS/NO signaling axis, as well as downregulated KLF4 expression and translocation to the nucleus. Compared with the SAL + siKLF4 co-administration group, no significant differences were observed in the expression levels of the phenotypic markers in the SAL or siKLF4 groups. In conclusion, the findings of the present study revealed that SAL may inhibit Hcy-induced EndMT via regulation of the KLF4/eNOS signaling pathway.

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EOFAZ inhibits endothelial‑to‑mesenchymal transition through downregulation of KLF4

Cited by 12 publications

References 52 publications

MED1 Regulates BMP/TGF-β in Endothelium: Implication for Pulmonary Hypertension

MED1 Regulates BMP/TGF-β in Endothelium: Implication for Pulmonary Hypertension

Chemical characterization and effects of volatile oil of Alpinia zerumbet on the quality of collagen deposition and caveolin-1 expression in a muscular fibrosis murine model

Salidroside inhibits endothelial‑mesenchymal transition via the KLF4/eNOS signaling pathway

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