Hydrogen sulfide suppresses endoplasmic reticulum stress-induced endothelial-to-mesenchymal transition through Src pathway

Ren, Ying; Wang, Xiaoqiao; Yang, Ying; Gu, Zhen-Jie; Mai, Jing-Ting; Qiu, Qiong; Chen, Yangxin; Wang, Jingfeng

doi:10.1016/j.lfs.2015.11.025

Cited by 55 publications

(29 citation statements)

References 47 publications

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“…However, the emerging understanding of macrophage subsets and their functions in atherosclerotic plaque has led to the consensus that M1 macrophages are pro-atherogenic, while M2 macrophages may promote plaque stability (27,28,45), primarily though their tissue repair and anti-inflammatory properties. Additionally, our previous study demonstrated that EndMT damaged endothelial tube formation capacity in an in vitro angiogenesis assay (46), which is consistent with our present results.…”

Section: Discussionsupporting

confidence: 93%

Macrophage-derived foam cells impair endothelial barrier function by inducing endothelial-mesenchymal transition via CCL-4

Yang

Luo

Ren

et al. 2017

International Journal of Molecular Medicine

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Recently, endothelial-mesenchymal transition (EndMT) has been demonstrated to play an important role in the development of atherosclerosis, the molecular mechanisms of which remain unclear. In the present study, scanning electron microscopy directly revealed a widened endothelial space and immunohistofluorescence demonstrated that EndMT was increased in human aorta atherosclerotic plaques. M1 macrophage-derived foam cell (M1-FC) supernatants, but not M2 macrophage-derived foam cell (M2-FC) supernatants, induced EndMT. A protein array and enzyme-linked immunosorbent assay identified that the levels of several cytokines, including C-C motif chemokine ligand 4 (CCL-4) were increased in M1-FC supernatants, in which EndMT was promoted, accompanied by increased endothelial permeability and monocyte adhesion. Furthermore, anti-CCL-4 antibody abolished the effects of M1-FC supernatants on EndMT. At the same time, CCL-4 activated its receptor, C-C motif chemokine receptor-5 (CCR-5), and upregulated transforming growth factor-β (TGF-β) expression. Further experiments revealed that EndMT induced by CCL-4 was reversed by treatment with CCR-5 antagonist and the RNA-mediated knockdown of TGF-β. On the whole, the data of the present study suggest that M1-FCs induce EndMT by upregulating CCL-4, and increase endothelial permeability and monocyte adhesion. These data may help to elucidate the important role of EndMT in the development of atherosclerosis.

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Section: Discussionsupporting

confidence: 93%

Macrophage-derived foam cells impair endothelial barrier function by inducing endothelial-mesenchymal transition via CCL-4

Yang

Luo

Ren

et al. 2017

International Journal of Molecular Medicine

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“…Our objective in the present study was to obtain the more representative gene expression profile in primary cells obtained from a pool of patients rather that extracted from a particular one, and to work with less precious and easily transfectable cells. The ability of HUVECs to undergo phenotypic conversion to mesenchymal cells has been demonstrated using various stimuli 34, 35 and here we show that ionizing radiation is another stimulus able to induce EndoMT in these human macrovascular cells, with a gene expression profile resembling the one obtained in irradiated HIMECs 15 . In vivo as well as in vitro , it is known that not all endothelial cells undergo EndoMT.…”

Section: Discussionsupporting

confidence: 63%

Endothelial Hey2 deletion reduces endothelial-to-mesenchymal transition and mitigates radiation proctitis in mice

Mintet

Lavigne

Paget

et al. 2017

Sci Rep

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The current study evaluated the role of Hey2 transcription factor in radiation-induced endothelial-to-mesenchymal transition (EndoMT) and its impact on radiation-induced tissue damage in mice. Phenotypic modifications of irradiated, Hey2 siRNA- and Hey2 vector plasmid-transfected human umbilical vein endothelial cells (HUVECs) resembling EndoMT were monitored by qPCR, immunocytochemistry and western blots. Subsequently, in mice, a Cre-LoxP strategy for inactivation of Hey2 specifically in the endothelium was used to study the biological consequences. Total body irradiation and radiation proctitis were monitored to investigate the impact of conditional Hey2 deletion on intestinal stem cells and microvascular compartment radiosensitivity, EndoMT and rectal damage severity. We found that EndoMT occurs in irradiated HUVECs with concomitant Hey2 mRNA and protein increase. While Hey2 silencing has no effect on radiation-induced EndoMT in vitro, Hey2 overexpression is sufficient to induce phenotypic conversion of endothelial cells. In mice, the conditional deletion of Hey2 reduces EndoMT frequency and the severity of rectal tissue damage. Our data indicate that the reduction in mucosal damage occurs through decline in stem/clonogenic epithelial cell loss mediated by microvascular protection. EndoMT is involved in radiation proctitis and this study demonstrates that a strategy based on the reduction of EndoMT mitigates intestinal tissue damage.

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“…Yadav et al found that H 2 S could inhibit PP1c via sulfhydration at Cys127, block the dephosphylation of eIF2α and therefore regulate the ERS ( Yadav et al, 2017 ). Some new pathways by which H 2 S controls ERS have been recently disclosed, including Akt-heat shock protein 90 pathway ( Xie et al, 2012 ), brain-derived neurotrophic factor-TrkB pathway ( Wei et al, 2014 ), silent mating type information regulator 2 homolog 1 ( Li et al, 2014 ), and Src pathway ( Ying et al, 2016 ), etc. However, most of these studies focused on turnon/off of the protein but not the S -sulfhydrated protein, nor the specific cysteine affected by H 2 S stimulation.…”

Section: Sulfhydration Mediates H 2 S-induced Biolmentioning

confidence: 99%

H2S-Induced Sulfhydration: Biological Function and Detection Methodology

et al. 2017

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At appropriate concentrations, hydrogen sulfide, a well-known gasotransmitter, plays important roles in both physiology and pathophysiology. Increasing evidence suggests that modifying thiol groups of specific cysteines in target proteins via sulfhydration or persulfidation is one of the important mechanisms responsible for the biological functions of hydrogen sulfide. A variety of key proteins of different cellular pathways in mammals have been reported to be sulfhydrated by hydrogen sulfide to participate and regulate the processes of cell survival/death, cell differentiation, cell proliferation/hypertrophy, cellular metabolism, mitochondrial bioenergetics/biogenesis, endoplasmic reticulum stress, vasorelaxtion, inflammation, oxidative stress, etc. Moreover, S-sulfhydration also exerts many biological functions through the cross-talk with other post-translational modifications including phosphorylation, S-nitrosylation and tyrosine nitration. This review summarizes recent studies of hydrogen sulfide-induced sulfhydration as a posttranslational modification, an important biological function of hydrogen sulfide, and sulfhydrated proteins are introduced. Additionally, we discuss the main methods of detecting sulfhydration of proteins.

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Hydrogen sulfide suppresses endoplasmic reticulum stress-induced endothelial-to-mesenchymal transition through Src pathway

Cited by 55 publications

References 47 publications

Macrophage-derived foam cells impair endothelial barrier function by inducing endothelial-mesenchymal transition via CCL-4

Macrophage-derived foam cells impair endothelial barrier function by inducing endothelial-mesenchymal transition via CCL-4

Endothelial Hey2 deletion reduces endothelial-to-mesenchymal transition and mitigates radiation proctitis in mice

H2S-Induced Sulfhydration: Biological Function and Detection Methodology

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