scholarly journals Oestrogen and progesterone inhibit the stimulated production of endothelin-1

1998 ◽  
Vol 330 (3) ◽  
pp. 1097-1105 ◽  
Author(s):  
K. Anjali MOREY ◽  
Mahnaz RAZANDI ◽  
Ali PEDRAM ◽  
Ren-Ming HU ◽  
A. Bruce PRINS ◽  
...  
Keyword(s):  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Activator Protein 1 ◽  
Protective Effects ◽  
Cellular Mechanisms ◽  
Aortic Endothelial Cells ◽  
Endothelin 1 ◽  
Mitogen Activated Protein ◽  
Erk Activity ◽  
Stimulation Of

Important vascular proteins such as endothelin-1 (ET-1) promote the development of cardiovascular diseases. Oestrogen, and perhaps progesterone, prevent the development of vascular disease in women through incompletely understood cellular mechanisms. We hypothesized that oestradiol or progesterone might regulate the production of ET-1 as a potential novel mechanism. We found that serum and angiotensin II (AII) significantly stimulated ET-1 secretion from cultured bovine aortic endothelial cells, inhibited 50-75% by oestradiol or by progesterone. Serum and AII stimulated ET-1 mRNA levels, inhibited at least 70% by oestradiol and by progesterone. Serum stimulated ET-1 transcription mainly through the first 43 nucleotides of the ET-1 promoter, but oestradiol and progesterone did not inhibit this. In contrast, AII stimulated ET-1 transcription through nucleotides -143 to -98, specifically involving an activator protein-1 (AP-1) site at -102. Oestradiol and progesterone caused a 60-70% inhibition of AII-stimulated wild-type construct -.143ET-1/CAT activity (CAT is chloramphenicol acyltransferase). AII-stimulation of ET-1 transcription was critically dependent on stimulation of mitogen-activated protein kinase (erk) activity, inhibited by oestradiol and progesterone. In summary, we found that sex steroids inhibit AII-induced erk signalling to the ET-1 transcriptional programme. This novel mechanism of negative transcriptional regulation by oestradiol and progesterone decreases the production of ET-1, potentially contributing to the vascular protective effects of these steroids.

scholarly journals MSKs are required for the transcription of the nuclear orphan receptors Nur77, Nurr1 and Nor1 downstream of MAPK signalling

2005 ◽  
Vol 390 (3) ◽  
pp. 749-759 ◽  
Author(s):  
Joanne Darragh ◽  
Ana Soloaga ◽  
Victoria A. Beardmore ◽  
Andrew D. Wingate ◽  
Giselle R. Wiggin ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Camp Response Element Binding ◽  
Mitogen Activated Protein Kinase ◽  
Early Gene ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Activator Protein 1 ◽  
Double Knockout ◽  
Mitogen Activated Protein

MSK (mitogen- and stress-activated protein kinase) 1 and MSK2 are kinases activated downstream of either the ERK (extracellular-signal-regulated kinase) 1/2 or p38 MAPK (mitogen-activated protein kinase) pathways in vivo and are required for the phosphorylation of CREB (cAMP response element-binding protein) and histone H3. Here we show that the MSKs are involved in regulating the transcription of the immediate early gene Nur77. Stimulation of mouse embryonic fibroblasts with PMA, EGF (epidermal growth factor), TNF (tumour necrosis factor) or anisomycin resulted in induction of the Nur77 mRNA. The induction of Nur77 by TNF and anisomycin was abolished in MSK1/2 double-knockout cells, whereas induction was significantly reduced in response to PMA or EGF. The MSK responsive elements were mapped to two AP (activator protein)-1-like elements in the Nur77 promoter. The induction of Nur77 was also blocked by A-CREB, suggesting that MSKs control Nur77 transcription by phosphorylating CREB bound to the two AP-1-like elements. Consistent with the decrease in Nur77 mRNA levels in the MSK1/2-knockout cells, it was also found that MSKs were required for the induction of Nur77 protein by PMA and TNF. MSKs were also found to be required for the transcription of two genes related to Nur77, Nurr1 and Nor1, which were also transcribed in a CREB- or ATF1 (activating transcription factor-1)-dependent manner. Downstream of anisomycin signalling, a second ERK-dependent pathway, independent of MSK and CREB, was also required for the transcription of Nurr1 and Nor1.

scholarly journals Loss of E-Cadherin–mediated Cell–Cell Contacts Activates a Novel Mechanism for Up-Regulation of the Proto-Oncogene c-Jun

2009 ◽  
Vol 20 (7) ◽  
pp. 2121-2129 ◽  
Author(s):  
Revital Knirsh ◽  
Iris Ben-Dror ◽  
Barbara Spangler ◽  
Gideon D. Matthews ◽  
Silke Kuphal ◽  
...  
Keyword(s):  
Cell Separation ◽  
Tumor Promotion ◽  
Mitogen Activated Protein Kinase ◽  
Cell Contact ◽  
Activator Protein 1 ◽  
Cell Contacts ◽  
Mitogen Activated Protein ◽  
Stimulation Of ◽  
E Cadherin ◽  
Cell Cell

Loss of E-cadherin–mediated cell–cell contacts can elicit a signaling pathway that leads to acquisition of an invasive phenotype. Here, we show that at the receiving end of this pathway is the proto-oncogene c-Jun, a member of the activator protein-1 family of transcription factors that play a key role in stimulation of cell proliferation and tumor promotion. Cell separation or abrogation of E-cadherin–mediated cell–cell contacts both cause a dramatic increase in accumulation of the c-Jun protein. Unlike growth factors that enhance the expression of c-Jun by activating the transcription of the c-jun gene, the cell contact-dependent increase in c-Jun accumulation is not accompanied by a corresponding increase in c-Jun mRNA or c-Jun protein stability but rather in the translatability of the c-Jun transcript. Consistently, the increase in c-Jun accumulation is not dependent on activation of the mitogen-activated protein kinase or β-catenin pathways but is mediated by signals triggered by the restructured cytoskeleton. Depolymerization of the cytoskeleton can mimic the effect of cell separation and cause a dramatic increase in c-Jun accumulation, whereas Taxol inhibits the cell contact-dependent increase. This novel mechanism of c-Jun regulation seems to underlie the robust overexpression of c-Jun in tumor cells of patients with colon carcinoma.

Factor VIIa stimulates endothelin-1 synthesis in TNF-primed endothelial cells by activation of protease-activated receptor 2

2005 ◽  
Vol 108 (3) ◽  
pp. 255-263 ◽  
Author(s):  
Amarjit S. SETHI ◽  
Delphine M. LEES ◽  
Julie A. DOUTHWAITE ◽  
Roger CORDER
Keyword(s):  
Endothelial Cells ◽  
Factor Viia ◽  
Mitogen Activated Protein Kinase ◽  
Factor Vii ◽  
Factor X ◽  
Aortic Endothelial Cells ◽  
Endothelin 1 ◽  
Mitogen Activated Protein ◽  
Factor Α ◽  
Protease Activated Receptor 2

The mechanisms linking prothrombotic changes to endothelial dysfunction and accelerated atheroma formation have yet to be fully defined. Expression of TF (tissue factor) on the endothelium is potentially an initiating event as binding and activation of FVII (factor VII) can result in thrombosis. Although PAR2 (protease-activated receptor-2) is expressed on vascular endothelium, its precise physiological significance and mechanism of activation have yet to be defined. In the present study, we investigated whether PAR2 can be activated by FVIIa (activated FVII) and induce ET-1 (endothelin-1) synthesis. In bovine aortic endothelial cells pretreated with TNF (tumour necrosis factor-α) to increase TF expression, FVIIa stimulated ET-1 synthesis via activation of PAR2. Although FX (factor X) alone was inactive, this response was enhanced by using FVII and FX in combination. Inhibition of the proteolytic activity of FVIIa abolished the response. The PAR2 agonist peptide SLIGKV also enhanced ET-1 release on TNF-pretreated cells. The response to FVIIa was inhibited by a PAR2 antagonist peptide FSLLRY. Inhibition of the p38 MAPK (mitogen-activated protein kinase) reduced PAR2 expression and the ET-1 response. In summary, FVIIa can stimulate ET-1 synthesis in endothelial cells by activating PAR2, demonstrating a potential link between thrombotic processes and endothelial cell dysfunction.

scholarly journals Crataegus laevigata Suppresses LPS-Induced Oxidative Stress during Inflammatory Response in Human Keratinocytes by Regulating the MAPKs/AP-1, NFκB, and NFAT Signaling Pathways

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 869
Author(s):  
Quynh T. N. Nguyen ◽  
Minzhe Fang ◽  
Mengyang Zhang ◽  
Nhung Quynh Do ◽  
Minseon Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Human Keratinocytes ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Protective Effects ◽  
Activated T Cells ◽  
Crataegus Laevigata ◽  
Mitogen Activated Protein

Crataegus laevigata belongs to the family Rosaceae, which has been widely investigated for pharmacological effects on the circulatory and digestive systems. However, there is limited understanding about its anti-oxidative stress and anti-inflammatory effects on skin. In this study, 70% ethanol C. laevigata berry extract (CLE) was investigated on lipopolysaccharide (LPS)-stimulated keratinocytes. The LPS-induced overproduction of reactive oxygen species (ROS) was suppressed by the treatment with CLE. In response to ROS induction, the overexpression of inflammatory regulating signaling molecules including mitogen-activated protein kinases (MAPK)/activator protein-1 (AP-1), nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB), and nuclear factor of activated T-cells (NFAT) were reduced in CLE-treated human keratinocytes. Consequently, CLE significantly suppressed the mRNA levels of pro-inflammatory chemokines and interleukins in LPS-stimulated cells. Our results indicated that CLE has protective effects against LPS-induced injury in an in vitro model and is a potential alternative agent for inflammatory treatment.

MKK3-p38 signaling promotes apoptosis and the early inflammatory response in the obstructed mouse kidney

2007 ◽  
Vol 293 (5) ◽  
pp. F1556-F1563 ◽  
Author(s):  
Frank Y. Ma ◽  
Greg H. Tesch ◽  
Richard A. Flavell ◽  
Roger J. Davis ◽  
David J. Nikolic-Paterson
Keyword(s):  
Inflammatory Response ◽  
P38 Mapk ◽  
Renal Injury ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Direct Role ◽  
Mitogen Activated Protein ◽  
Early Inflammatory Response ◽  
Induced Apoptosis

Activation of the p38 mitogen-activated protein kinase (MAPK) pathway induces inflammation, apoptosis, and fibrosis. However, little is known of the contribution of the upstream kinases, MMK3 and MKK6, to activation of the p38 kinase in the kidney and consequent renal injury. This study investigated the contribution of MKK3 to p38 MAPK activation and renal injury in the obstructed kidney. Groups of eight wild-type (WT) or Mkk3−/− mice underwent unilateral ureteric obstruction (UUO) and were killed 3 or 7 days later. Western blotting showed a marked increase in phospho-p38 (p-p38) MAPK in UUO WT kidney. The same trend of increased p-p38 MAPK was seen in the UUO Mkk3−/− kidney, although the actual level of p-p38 MAPK was significantly reduced compared with WT, and this could not be entirely compensated for by the increase in MKK6 expression in the Mkk3−/− kidney. Apoptosis of tubular and interstitial cells in WT UUO mice was reduced by 50% in Mkk3−/− UUO mice. Furthermore, cultured Mkk3−/− tubular epithelial cells showed resistance to H2O2-induced apoptosis, suggesting a direct role for MKK3-p38 signaling in tubular apoptosis. Upregulation of MCP-1 mRNA levels and macrophage infiltration seen on day 3 in WT UUO mice was significantly reduced in Mkk3−/− mice, but this difference was not evident by day 7. The development of renal fibrosis in Mkk3−/− UUO mice was not different from that seen in WT UUO mice. In conclusion, these studies identify discrete roles for MKK3-p38 signaling in renal cell apoptosis and the early inflammatory response in the obstructed kidney.

Sign in / Sign up

Export Citation Format

Share Document