Cyclosporin A upregulates ETB receptor in vascular smooth muscle via activation of mitogen-activating protein kinases and NF-κB pathways

Zheng, Jing; Cheng, Zhuoan; Jiang, Jiaye; Ke, Ya; Liu, Zongjun

doi:10.1016/j.toxlet.2015.03.004

Cited by 14 publications

(8 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Multiple studies demonstrated that the activity of C/EBP β, c-Fos and HIF-1αis also regulated by posttranslational modification caused by phosphorylation by different kinases, such as MAPK, cdc2, PKA and PKC1617484950. Previous studies targeted the effects of ERK1/2 pathways on GPR91-dependent VEGF expression in the retinas of streptozotocin-induced diabetic rats7.…”

Section: Discussionmentioning

confidence: 99%

Transcription factors regulate GPR91-mediated expression of VEGF in hypoxia-induced retinopathy

Gao

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Hypoxia is the most important factor in the pathogenesis of diabetic retinopathy (DR). Our previous studies demonstrated that G protein-coupled receptor 91(GPR91) participated in the regulation of vascular endothelial growth factor (VEGF) secretion in DR. The present study induced OIR model in newborn rats using exposure to alternating 24-hour episodes of 50% and 12% oxygen for 14 days. Treatment with GPR91 shRNA attenuated the retinal avascular area, abnormal neovascularization and pericyte loss. Western blot and qRT-PCR demonstrated that CoCl2 exposure promoted VEGF expression and secretion, activated the ERK1/2 signaling pathways and upregulated C/EBP and AP-1. Knockdown of GPR91 inhibited ERK1/2 activity. GPR91 siRNA transduction and the ERK1/2 inhibitor U0126 inhibited the increases in C/EBP β, C/EBP δ, c-Fos and HIF-1α. Luciferase reporter assays and a chromatin immunoprecipitation (ChIP) assay demonstrated that C/EBP β and c-Fos bound the functional transcriptional factor binding site in the region of the VEGF promoter, but not C/EBP δ. Knockdown of C/EBP β and c-Fos using RNAi reduced VEGF expression. Our data suggest that activation of the GPR91-ERK1/2-C/EBP β (c-Fos, HIF-1α) signaling pathway plays a tonic role in regulating VEGF transcription in rat retinal ganglion cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Transcription factors regulate GPR91-mediated expression of VEGF in hypoxia-induced retinopathy

Gao

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Under a normal physiological state, the ET B receptor is primarily expressed on vascular endothelial cells to mediate dilation. In pathological conditions, the ET B receptor is expressed in vascular smooth muscle to mediate the vasoconstriction reaction, during which the ET B receptor undergoes a process from absence to presence on vascular smooth muscle . However, the mechanism underlying the intracellular change remains unclear .…”

Section: Discussionmentioning

confidence: 99%

Minimally modified low-density lipoprotein upregulates the ETB and α1 receptors in mouse mesenteric arteries in vivo by activating the PI3K/Akt pathway

Zeng

Lin

et al. 2019

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

Objectives The current study aimed to explore whether minimally modified low‐density lipoprotein (mmLDL) via tail vein injection upregulates the ETB and α1 receptors in mouse mesenteric arteries by activating the PI3K/Akt pathway. Methods The contraction curves of the mesenteric arteries caused by sarafotoxin 6c (S6c, ETB receptor agonist) and phenylephrine (PE, α1 receptor agonist) were measured by a myograph system. Serum oxLDL was detected using enzyme‐linked immunosorbent assays. The levels of the ETB receptor, the α1 receptor, PI3K, p‐PI3K and p‐Akt were detected using real‐time polymerase chain reaction and Western blot analyses. Key findings Minimally modified low‐density lipoprotein noticeably enhanced the contraction effect curves of S6c and PE, with significantly increased Emax values (P < 0.01), compared to those of the control group. This treatment significantly increased the mRNA expression and protein levels of the ETB and α1 receptors and the protein levels of p‐PI3K and p‐Akt in the vessel wall (P < 0.01). LY294002 inhibited the effect of mmLDL. Conclusions An increase in mmLDL activated the PI3K/Akt pathway, which upregulated the expression of the ETB and α1 receptors and enhanced the ETB and α1‐receptor‐mediated contractile function.

show abstract

“…A number of studies which have used cell cultures, tried to explain the action and cause of side effects of CsA: among others, excessive proliferation, diabetes, hypertension, and the increased risk of non-melanoma skin cancers, especially squamous cell carcinoma [ 21 , 22 , 23 , 24 ]. A previous study proved that steroidogenesis and CYPs are involved in the pathology of skin cancer [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Potential Mechanism of Action of Cyclosporin A in Human Dermal Fibroblasts—Transcriptomic Analysis of CYPs

et al. 2018

View full text Add to dashboard Cite

Effect of cyclosporin A (CsA) in a therapeutic concentration, on the expression of cytochrome P450 genes (CYPs), was investigated in normal human dermal fibroblast cells. The expression of 57 genes, encoding cytochrome P450 isoforms, was estimated using the microarray method. Amongst 396 normalized fluorescence signals related to cytochrome P450 activity, only 91 were strictly connected to CYPs and were analyzed using two methods: a self-organizing feature map of artificial neural networks and typical statistical analysis with significance level at p ≤ 0.05. Comparing the samples from fibroblasts cultured with CsA and those cultured without, up-regulated changes of CYP19A1, 1B1, 7A1, 7F1, 17A1 and down-regulated 2D6 gene expression were observed. The mRNAs with increased changes were in the same neuron of the self-organizing feature map. All distinguished CYPs encode monooxygenases, which plays an important role in steroids biosynthesis and metabolism. Based on the obtained results, we can conclude that CsA in therapeutic concentration changes the expression profile of CYPs in human dermal fibroblasts, especially affecting genes linked to steroids synthesis and/or metabolism. It shows the potential mechanism of action of CsA in human dermal fibroblast cells.

show abstract

Cyclosporin A upregulates ETB receptor in vascular smooth muscle via activation of mitogen-activating protein kinases and NF-κB pathways

Cited by 14 publications

References 26 publications

Transcription factors regulate GPR91-mediated expression of VEGF in hypoxia-induced retinopathy

Transcription factors regulate GPR91-mediated expression of VEGF in hypoxia-induced retinopathy

Minimally modified low-density lipoprotein upregulates the ETB and α1 receptors in mouse mesenteric arteries in vivo by activating the PI3K/Akt pathway

Potential Mechanism of Action of Cyclosporin A in Human Dermal Fibroblasts—Transcriptomic Analysis of CYPs

Contact Info

Product

Resources

About