scholarly journals Intermittent High Glucose Elevates Nuclear Localization of EZH2 to Cause H3K27me3-Dependent Repression of KLF2 Leading to Endothelial Inflammation

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2548
Author(s):  
Sumukh Thakar ◽  
Yash T Katakia ◽  
Shyam Kumar Ramakrishnan ◽  
Niyati Pandya Pandya Thakkar ◽  
Syamantak Majumder
Keyword(s):  
High Glucose ◽  
Rat Aorta ◽  
Gene Promoters ◽  
Epigenetic Mechanisms ◽  
Nuclear Retention ◽  
Polycomb Repressive Complex 2 ◽  
Protein Levels ◽  
Endothelial Inflammation ◽  
Treatment Conditions ◽  
Intermittent High Glucose

Epigenetic mechanisms have emerged as one of the key pathways promoting diabetes-associated complications. Herein, we explored the role of enhancer of zeste homolog 2 (EZH2) and its product histone 3 lysine 27 trimethylation (H3K27me3) in high glucose-mediated endothelial inflammation. To examine this, we treated cultured primary endothelial cells (EC) with different treatment conditions—namely, constant or intermittent or transient high glucose. Intermittent high glucose maximally induced endothelial inflammation by upregulating transcript and/or protein-level expression of ICAM1 and P-selectin and downregulating eNOS, KLF2, and KLF4 protein levels. We next investigated the underlining epigenetic mechanisms responsible for intermittent hyperglycemia-dependent endothelial inflammation. Compared with other high glucose treatment groups, intermittent high glucose-exposed EC exhibited an increased level of H3K27me3 caused by reduction in EZH2 threonine 367 phosphorylation and nuclear retention of EZH2. Intermittent high glucose also promoted polycomb repressive complex-2 (PRC2) assembly and EZH2′s recruitment to histone H3. Abrupt enrichment of H3K27me3 on KLF2 and KLF4 gene promoters caused repression of these genes, further supporting endothelial inflammation. In contrast, reducing H3K27me3 through small molecule and/or siRNA-mediated inhibition of EZH2 rescued KLF2 level and inhibited endothelial inflammation in intermittent high glucose-challenged cultured EC and isolated rat aorta. These findings indicate that abrupt chromatin modifications cause high glucose-dependent inflammatory switch of EC.

High Glucose/Thrombin-Induced Endothelial Inflammation Via Microrna-146a and Nox4 Regulation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5952-5952
Author(s):  
Ching-Tien Peng ◽  
Wan Yu Lo ◽  
Huang Joe Wang
Keyword(s):  
High Glucose ◽  
Conflicts Of Interest ◽  
Mrna Level ◽  
In Silico Analysis ◽  
Fold Increase ◽  
Ros Generation ◽  
Aortic Endothelial Cells ◽  
Protein Levels ◽  
Endothelial Inflammation

Abstract Diabetes is associated with hyperglycemia and increased thrombin generation. It is unknown whether high glucose (HG)/thrombin can modulate the expression of NAPDH oxidase (Nox) subtypes in human aortic endothelial cells (HAECs). Besides, we investigate whether miR-146a is involved in endothelial cell inflammation. We observed that HG (25 mmol/l) exerted a synergistic effect with thrombin (2 U/ml) for induction of Nox4 mRNA level in HAECs. The increased Nox4 mRNA was associated with increased Nox4 protein and ROS production. We also demonstrated that HG/thrombin treatment increased interleukin-8 and interleukin-6 protein levels. Besides, HG/thrombin treatment caused an 11.43-fold increase of THP-1 adhesion to HAECs. In Silico analysis identified homology between miR-146a and the 3’-UTR of the human Nox4 mRNA, suggesting a potential regulation of Nox4 by miR-146a. Furthermore, HG/thrombin treatment decreased miR146a expression to 58% of the control, indicating an impaired feedback restrain of HG/thrombin-induced endothelial inflammation. MiR-146a mimic transfection prevented HG/thrombin-induced upregulation of Nox4 mRNA, Nox4 protein, and ROS generation. In addition, inflammatory phenotypes were attenuated in miR-146a mimic-transfected HAECs. In conclusion, miR-146a is involved in the regulation of endothelial inflammation via modulation of Nox4 in an in-vitro milieu mimicking diabetic atherothrombosis. Disclosures No relevant conflicts of interest to declare.

Acute glucose-induced downregulation of PKC-βII accelerates cultured VSMC proliferation

2000 ◽  
Vol 279 (3) ◽  
pp. C587-C595 ◽  
Author(s):  
Mayumi Yamamoto ◽  
Mildred Acevedo-Duncan ◽  
Charles E. Chalfant ◽  
Niketa A. Patel ◽  
James E. Watson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Dna Synthesis ◽  
High Glucose ◽  
Cell Cycle Progression ◽  
Specific Inhibitor ◽  
Rat Aorta ◽  
Vsmc Proliferation ◽  
Protein Levels ◽  
Normal Glucose

Accelerated vascular smooth muscle cell (VSMC) proliferation contributes to the formation of atherosclerotic lesions. To investigate protein kinase C (PKC)-βII functions with regard to glucose-induced VSMC proliferation, human VSMC from aorta (AoSMC), a clonal VSMC line of rat aorta (A10), and A10 cells overexpressing PKC-βI (βI-A10) and PKC-βII (βII-A10) were studied with the use of three techniques to evaluate glucose effects on aspects affecting proliferation. High glucose (25 mM) increased DNA synthesis and accelerated cell proliferation compared with normal glucose (5.5 mM) in AoSMC and A10 cells, but not in βI-A10 and βII-A10 cells. The PKC-βII specific inhibitor CGP-53353 inhibited glucose-induced cell proliferation and DNA synthesis in AoSMC and A10 cells. In flow cytometry analysis, high glucose increased the percentage of A10 cells at 12 h after cell cycle initiation but did not increase the percentage of βI-A10 or βII-A10 cells entering S phase. PKC-βII protein levels decreased before the peak of DNA synthesis, and high glucose further decreased PKC-βII mRNA and protein levels in AoSMC and A10 cells. These results suggest that high glucose downregulates endogenous PKC-βII, which then alters the normal inhibitory role of PKC-βII in cell cycle progression, resulting in the stimulation of VSMC proliferation through acceleration of the cell cycle.

scholarly journals Transcriptional repression of SIRT1 by protein inhibitor of activated STAT 4 (PIAS4) in hepatic stellate cells contributes to liver fibrosis

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Lina Sun ◽  
Zhiwen Fan ◽  
Junliang Chen ◽  
Wenfang Tian ◽  
Min Li ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
High Glucose ◽  
Interstitial Fibrosis ◽  
Stellate Cells ◽  
Quiescent State ◽  
Dependent Manner ◽  
Gene Promoters ◽  
Sirt1 Expression ◽  
Primary Mouse

Abstract Interstitial fibrosis represents a key pathological process in non-alcoholic steatohepatitis (NASH). In the liver, fibrogenesis is primarily mediated by activated hepatic stellate cells (HSCs) transitioning from a quiescent state in response to a host of stimuli. The molecular mechanism underlying HSC activation is not completely understood. Here we report that there was a simultaneous up-regulation of PIAS4 expression and down-regulation of SIRT1 expression accompanying increased hepatic fibrogenesis in an MCD-diet induced mouse model of NASH. In cultured primary mouse HSCs, stimulation with high glucose activated PIAS4 while at the same time repressed SIRT1. Over-expression of PIAS4 directly repressed SIRT1 promoter activity. In contrast, depletion of PIAS4 restored SIRT1 expression in HSCs treated with high glucose. Estrogen, a known NASH-protective hormone, antagonized HSC activation by targeting PIAS4. Lentivirus-mediated delivery of short hairpin RNA (shRNA) targeting PIAS4 in mice ameliorated MCD diet induced liver fibrosis by normalizing SIRT1 expression in vivo. PIAS4 promoted HSC activation in a SIRT1-dependent manner in vitro. Mechanistically, PIAS4 mediated SIRT1 repression led to SMAD3 hyperacetylation and enhanced SMAD3 binding to fibrogenic gene promoters. Taken together, our data suggest SIRT1 trans-repression by PIAS4 plays an important role in HSC activation and liver fibrosis.

scholarly journals (Pro)renin receptor regulates autophagy and apoptosis in podocytes exposed to high glucose

2015 ◽  
Vol 309 (3) ◽  
pp. E302-E310 ◽  
Author(s):  
Caixia Li ◽  
Helmy M. Siragy
Keyword(s):  
Signaling Pathway ◽  
High Glucose ◽  
Caspase 3 ◽  
Mtor Signaling ◽  
Autophagic Flux ◽  
Bafilomycin A1 ◽  
Mtor Signaling Pathway ◽  
Autophagosome Formation ◽  
Podocyte Injury ◽  
Protein Levels

High glucose reduces autophagy and enhances apoptosis of podocytes. Previously, we reported that high glucose induced podocyte injury through upregulation of the (pro)renin receptor (PRR). We hypothesized that increasing PRR reduces autophagy and increases apoptosis of mouse podocytes exposed to high glucose via activation of the PI3K/Akt/mTOR signaling pathway. Mouse podocytes were cultured in normal (5 mmol/l) or high (25 mmol/l) d-glucose for 48 h. High glucose significantly increased mRNA and protein levels of PRR, phosphorylation of PI3K/Akt/mTOR, and p62. In contrast, high glucose decreased activation of UNC-51-like kinase-1 (ULK1) by phosphorylating Ser757 and protein levels of microtubule-associated protein-1 light chain 3B (LC3B)-II and Lamp-2. Bafilomycin A1 increased LC3BII and p62 accumulation in high-glucose-treated cells. High glucose reduced the autophagic flux. Confocal microscopy studies showed significant reduction in the protein level of LC3B in response to high glucose. Cyto-ID autophagy staining showed a significant decrease in autophagosome formation with high glucose. In the absence of PRR, activation of Akt with sc-79 or mTOR with MHY-1485 increased p62 accumulation. Caspase-3/7 activity and apoptosis monitored by TUNEL assay were significantly increased in podocytes treated with high glucose. PRR siRNA significantly reversed the effects of high glucose. Based on these data, we conclude that high glucose decreases autophagy and increases apoptosis in mouse podocytes through the PRR/PI3K/Akt/mTOR signaling pathway.

scholarly journals Ginsenoside Rg3 prevents INS-1 cell death from intermittent high glucose stress

Islets ◽  
2016 ◽  
Vol 8 (3) ◽  
pp. 57-64 ◽  
Author(s):  
You Jeong Kim ◽  
Su Min Park ◽  
Hye Sook Jung ◽  
Eun Ju Lee ◽  
Tae Kyoon Kim ◽  
...  
Keyword(s):  
Cell Death ◽  
High Glucose ◽  
Ginsenoside Rg3 ◽  
Intermittent High Glucose

Epigenetic control of cellular senescence in disease: opportunities for therapeutic intervention

2007 ◽  
Vol 9 (7) ◽  
pp. 1-26 ◽  
Author(s):  
Stuart P. Atkinson ◽  
W. Nicol Keith
Keyword(s):  
Gene Expression ◽  
Cellular Senescence ◽  
Chromatin Remodelling ◽  
Telomere Maintenance ◽  
Cell Physiology ◽  
Gene Promoters ◽  
Epigenetic Mechanisms ◽  
Histone Proteins ◽  
Regulate Gene Expression ◽  
Regulate Gene

AbstractUnderstanding how senescence is established and maintained is an important area of study both for normal cell physiology and in tumourigenesis. Modifications to N-terminal tails of histone proteins, which can lead to chromatin remodelling, appear to be key to the regulation of the senescence phenotype. Epigenetic mechanisms such as modification of histone proteins have been shown to be sufficient to regulate gene expression levels and specific gene promoters can become epigenetically altered at senescence. This suggests that epigenetic mechanisms are important in senescence and further suggests epigenetic deregulation could play an important role in the bypass of senescence and the acquisition of a tumourigenic phenotype. Tumour suppressor proteins and cellular senescence are intimately linked and such proteins are now known to regulate gene expression through chromatin remodelling, again suggesting a link between chromatin modification and cellular senescence. Telomere dynamics and the expression of the telomerase genes are also both implicitly linked to senescence and tumourigenesis, and epigenetic deregulation of the telomerase gene promoters has been identified as a possible mechanism for the activation of telomere maintenance mechanisms in cancer. Recent studies have also suggested that epigenetic deregulation in stem cells could play an important role in carcinogenesis, and new models have been suggested for the attainment of tumourigenesis and bypass of senescence. Overall, proper regulation of the chromatin environment is suggested to have an important role in the senescence pathway, such that its deregulation could lead to tumourigenesis.

scholarly journals Astragaloside IV Suppresses High Glucose-Induced NLRP3 Inflammasome Activation by Inhibiting TLR4/NF-κB and CaSR

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Bin Leng ◽  
Yingjie Zhang ◽  
Xinran Liu ◽  
Zhen Zhang ◽  
Yang Liu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
High Glucose ◽  
Inflammasome Activation ◽  
Astragaloside Iv ◽  
Caspase 1 ◽  
Endothelial Inflammation ◽  
Nlrp3 Inflammasome Activation ◽  
Anti Inflammatory

Long-term exposure to high glucose induces vascular endothelial inflammation that can result in cardiovascular disease. Astragaloside IV (As-IV) is widely used for anti-inflammatory treatment of cardiovascular diseases. However, its mechanism of action is still not fully understood. In this study, we investigated the effect of As-IV on high glucose-induced endothelial inflammation and explored its possible mechanisms. In vivo, As-IV (40 and 80 mg/kg/d) was orally administered to rats for 8 weeks after a single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg). In vitro, human umbilical vein endothelial cells (HUVECs) were treated with high glucose (33 mM glucose) in the presence or absence of As-IV, NPS2143 (CaSR inhibitor), BAY 11-7082 (NF-κB p65 inhibitor), and INF39 (NLRP3 inhibitor), and overexpression of CaSR was induced by infection of CaSR-overexpressing lentiviral vectors to further discuss the anti-inflammatory property of As-IV. The results showed that high glucose increased the expression of interleukin-18 (IL-18), interleukin-1β (IL-1β), NLRP3, caspase-1, and ASC, as well as the protein level of TLR4, nucleus p65, and CaSR. As-IV can reverse these changes in vivo and in vitro. Meanwhile, NPS2143, BAY 11-7082, and INF39 could significantly abolish the high glucose-enhanced NLRP3, ASC, caspase-1, IL-18, and IL-1β expression in vitro. In addition, both NPS2143 and BAY 11-7082 attenuated high glucose-induced upregulation of NLRP3, ASC, caspase-1, IL-18, and IL-1β expression. In conclusion, this study suggested that As-IV could inhibit high glucose-induced NLRP3 inflammasome activation and subsequent secretion of proinflammatory cytokines via inhibiting TLR4/NF-κB signaling pathway and CaSR, which provides new insights into the anti-inflammatory activity of As-IV.

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