High glucose-mediated effects on endothelial cell proliferation occur via p38 MAP kinase

2003 ◽  
Vol 285 (4) ◽  
pp. E708-E717 ◽  
Author(s):  
S. McGinn ◽  
S. Saad ◽  
P. Poronnik ◽  
C. A. Pollock
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Growth ◽  
Map Kinase ◽  
High Glucose ◽  
Map Kinases ◽  
P38 Map Kinase ◽  
Human Endothelial Cells ◽  
Cell Hypertrophy ◽  
Tgf Β1

The mitogen-activated protein (MAP) kinases contribute to altered cell growth and function in a variety of disease states. However, their role in the endothelial complications of diabetes mellitus remains unclear. Human endothelial cells were exposed for 72 h to 5 mM (control) or 25 mM (high) glucose or 5 mM glucose plus 20 mM mannitol (osmotic control). The roles of p38 and p42/44 MAP kinases in the high glucose-induced growth effects were determined by assessment of phosphorylated MAP kinases and their downstream activators by Western blot and by pharmacological inhibition of these MAP kinases. Results were expressed as a percentage (means ± SE) of control. High glucose increased the activity of total and phosphorylated p38 MAP kinase ( P < 0.001) and p42/44 MAP kinase ( P < 0.001). Coexposure of p38 MAP kinase blocker with high glucose reversed the antiproliferative but not the hypertrophic effects associated with high-glucose conditions. Transforming growth factor (TGF)-β1 increased the levels of phosphorylated p38 MAP kinase, and p38 MAP kinase blockade reversed the antiproliferative effects of this cytokine. The high glucose-induced increase in phosphorylated p38 MAP kinase was reversed in the presence of TGF-β1 neutralizing antibody. Although hyperosmolarity also induced antiproliferation ( P < 0.0001) and cell hypertrophy ( P < 0.05), there was no change in p38 activity, and therefore inhibition of p38 MAP kinase had no influence on these growth responses. Blockade of p42/44 MAP kinase had no effect on the changes in endothelial cell growth induced by either high glucose or hyperosmolarity. High glucose increased p42/44 and p38 MAP kinase activity in human endothelial cells, but only p38 MAP kinase mediated the antiproliferative growth response through the effects of autocrine TGF-β1. High glucose-induced endothelial cell hypertrophy was independent of activation of the MAP kinases studied. In addition, these effects were independent of any increase in osmolarity associated with high-glucose exposure.

Activation of p38 MAP Kinase and JNK But Not ERK Is Required for Erythropoietin-Induced Erythroid Differentiation

Blood ◽  
1998 ◽  
Vol 92 (6) ◽  
pp. 1859-1869 ◽  
Author(s):  
Yuka Nagata ◽  
Noriko Takahashi ◽  
Roger J. Davis ◽  
Kazuo Todokoro
Keyword(s):  
Cell Growth ◽  
Map Kinase ◽  
Antisense Oligonucleotides ◽  
Map Kinases ◽  
Physiological Function ◽  
Critical Role ◽  
Specific Inhibitor ◽  
Erythroid Differentiation ◽  
P38 Map Kinase ◽  
American Society

p38 MAP kinase (p38) and JNK have been described as playing a critical role in the response to a variety of environmental stresses and proinflammatory cytokines. It was recently reported that hematopoietic cytokines activate not only classical MAP kinases (ERK), but also p38 and JNK. However, the physiological function of these kinases in hematopoiesis remains obscure. We found that all MAP kinases examined, ERK1, ERK2, p38, JNK1, and JNK2, were rapidly and transiently activated by erythropoietin (Epo) stimulation in SKT6 cells, which can be induced to differentiate into hemoglobinized cells in response to Epo. Furthermore, p38-specific inhibitor SB203580 but not MEK-specific inhibitor PD98059 significantly suppressed Epo-induced differentiation and antisense oligonucleotides of p38, JNK1, and JNK2, but neither ERK1 nor ERK2 clearly inhibited Epo-induced hemoglobinization. However, in Epo-dependent FD-EPO cells, inhibition of either ERKs, p38, or JNKs suppressed cell growth. Furthermore, forced expression of a gain-of-function MKK6 mutant, which specifically activated p38, induced hemoglobinization of SKT6 cells without Epo. These results indicate that activation of p38 and JNKs but not of ERKs is required for Epo-induced erythroid differentiation of SKT6 cells, whereas all of these kinases are involved in Epo-induced mitogenesis of FD-EPO cells. © 1998 by The American Society of Hematology.

PEDF induces apoptosis in human endothelial cells by activating p38 MAP kinase dependent cleavage of multiple caspases

2006 ◽  
Vol 348 (4) ◽  
pp. 1288-1295 ◽  
Author(s):  
Leiling Chen ◽  
Samuel Shao-Min Zhang ◽  
Colin J. Barnstable ◽  
Joyce Tombran-Tink
Keyword(s):  
Endothelial Cells ◽  
Map Kinase ◽  
P38 Map Kinase ◽  
Human Endothelial Cells

Hyaluronidase enhancement of TNF-mediated cell death is reversed by TGF-β1

1997 ◽  
Vol 273 (6) ◽  
pp. C1987-C1994 ◽  
Author(s):  
Nan-Shan Chang
Keyword(s):  
Extracellular Matrix ◽  
Cell Death ◽  
Cell Growth ◽  
Map Kinase ◽  
Map Kinases ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
Lncap Cells ◽  
L929 Cells ◽  
Tgf Β1

Both hyaluronidase and transforming growth factor (TGF)-β1 play a significant role in the development of prostate cancer. In this study, the regulation of tumor necrosis factor (TNF)-mediated cell death by hyaluronidase and TGF-β1 was investigated. Preexposure of L929 fibroblasts, prostate LNCaP cells, and epithelial Mv 1 Lu cells to hyaluronidase for a minimum of 12 h resulted in significant enhancement of cell death by TNF. Phosphorylation of p42 and p44 mitogen-activated protein (MAP) kinases was found by stimulation of L929 cells with hyaluronidase for 30 min, indicating that the Raf/MAP kinase-extracellular signal-regulating protein kinase (MEK)/MAP kinase pathway was activated. However, blocking the activation of upstream MAP kinase kinase (MEK 1 and 2 kinase) by PD-98059 failed to inhibit the hyaluronidase-enhanced TNF killing of cells, suggesting that hyaluronidase-mediated degradation of extracellular matrix and membrane components may elicit multiple signaling pathways. As a potent stimulator of extracellular matrix protein synthesis, TGF-β1 blocked the hyaluronidase-enhanced death of L929 and LNCaP cells mediated by TNF. TGF-β1 activated protein-tyrosine kinases in L929 cells, in which the tyrosine kinase inhibitors lavendustin A and tyrphostin blocked the activation as well as the TGF-β1 inhibition of hyaluronidase effects. Functional antagonism was also observed between hyaluronidase and TGF-β1 in cell growth regulation. For example, TGF-β1-mediated suppression of epithelial Mv 1 Lu cell growth was abolished by hyaluronidase. Overall, it is demonstrated in this study that hyaluronidase reciprocally antagonized TGF-β1 in the modulation of cell proliferation and TNF-mediated death.

Activation of p38 MAP Kinase and JNK But Not ERK Is Required for Erythropoietin-Induced Erythroid Differentiation

Blood ◽  
1998 ◽  
Vol 92 (6) ◽  
pp. 1859-1869 ◽  
Author(s):  
Yuka Nagata ◽  
Noriko Takahashi ◽  
Roger J. Davis ◽  
Kazuo Todokoro
Keyword(s):  
Cell Growth ◽  
Map Kinase ◽  
Antisense Oligonucleotides ◽  
Map Kinases ◽  
Physiological Function ◽  
Critical Role ◽  
Specific Inhibitor ◽  
Erythroid Differentiation ◽  
P38 Map Kinase ◽  
American Society

Abstract p38 MAP kinase (p38) and JNK have been described as playing a critical role in the response to a variety of environmental stresses and proinflammatory cytokines. It was recently reported that hematopoietic cytokines activate not only classical MAP kinases (ERK), but also p38 and JNK. However, the physiological function of these kinases in hematopoiesis remains obscure. We found that all MAP kinases examined, ERK1, ERK2, p38, JNK1, and JNK2, were rapidly and transiently activated by erythropoietin (Epo) stimulation in SKT6 cells, which can be induced to differentiate into hemoglobinized cells in response to Epo. Furthermore, p38-specific inhibitor SB203580 but not MEK-specific inhibitor PD98059 significantly suppressed Epo-induced differentiation and antisense oligonucleotides of p38, JNK1, and JNK2, but neither ERK1 nor ERK2 clearly inhibited Epo-induced hemoglobinization. However, in Epo-dependent FD-EPO cells, inhibition of either ERKs, p38, or JNKs suppressed cell growth. Furthermore, forced expression of a gain-of-function MKK6 mutant, which specifically activated p38, induced hemoglobinization of SKT6 cells without Epo. These results indicate that activation of p38 and JNKs but not of ERKs is required for Epo-induced erythroid differentiation of SKT6 cells, whereas all of these kinases are involved in Epo-induced mitogenesis of FD-EPO cells. © 1998 by The American Society of Hematology.

Adenosine stimulates proliferation of human endothelial cells in culture

1993 ◽  
Vol 265 (1) ◽  
pp. H131-H138 ◽  
Author(s):  
M. F. Ethier ◽  
V. Chander ◽  
J. G. Dobson
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Growth ◽  
Cell Cultures ◽  
Umbilical Vein ◽  
Fibroblast Cell ◽  
Human Endothelial Cells ◽  
Cell Counts ◽  
Endothelial Cell Cultures ◽  
Endothelial Cell Growth

The effect of adenosine on proliferation of human endothelial cells was investigated by adding adenosine to the medium of cultures derived from human umbilical veins. Cell counts on cultures grown in 10 microM adenosine for 4–7 days were 41–53% greater than counts from control cultures. In contrast, 10 microM adenosine had no effect on growth of a human fibroblast cell strain (IMR-90). Neither inosine nor 2',5'-dideoxyadenosine influenced endothelial cell growth at concentrations of 0.1 or 10 microM. Addition of adenosine deaminase abolished the proliferative effect of added adenosine and inhibited proliferation by 16% in control cultures, suggesting that endogenous adenosine may enhance proliferation in culture. The adenosine receptor antagonist, 8-phenyltheophylline, at 0.1 and 1.0 microM blocked the enhanced proliferation caused by 10 microM adenosine. Addition of 10 microM adenosine enhanced DNA synthesis in endothelial cell cultures as indicated by an increased incorporation of [3H]thymidine into acid-insoluble cell material. The results indicate that addition of physiological concentrations of adenosine to human umbilical vein endothelial cell cultures stimulates proliferation, possibly via a surface receptor, and suggest that adenosine may be a factor for human endothelial cell growth and possibly angiogenesis.

scholarly journals Tiam1-Rac1 Axis Promotes Activation of p38 MAP Kinase in the Development of Diabetic Retinopathy: Evidence for a Requisite Role for Protein Palmitoylation

2015 ◽  
Vol 36 (1) ◽  
pp. 208-220 ◽  
Author(s):  
Rajakrishnan Veluthakal ◽  
Binit Kumar ◽  
Ghulam Mohammad ◽  
Anjaneyulu Kowluru ◽  
Renu A. Kowluru
Keyword(s):  
Endothelial Cells ◽  
Diabetic Retinopathy ◽  
Mitochondrial Dysfunction ◽  
Map Kinase ◽  
High Glucose ◽  
Cell Apoptosis ◽  
Metabolic Stress ◽  
P38 Map Kinase ◽  
Kinase Activation ◽  
Protein Palmitoylation

Background/Aims: Evidence in multiple tissues, including retina, suggests generation of reactive oxygen species (ROS) and the ensuing oxidative stress as triggers for mitochondrial defects and cell apoptosis. We recently reported novel roles for Tiam1-Rac1-Nox2 axis in retinal mitochondrial dysfunction and cell death leading to the development of diabetic retinopathy. Herein, we tested the hypothesis that activation of p38 MAP kinase, a stress kinase, represents the downstream signaling event to Rac1-Nox2 activation in diabetes-induced metabolic stress leading to capillary cell apoptosis. Methods: Activation of p38 MAP kinase was quantified by Western blotting in retinal endothelial cells incubated with high glucose (20 mM) for up to 96 hours, a duration where mitochondrial dysfunction and capillary cell apoptosis can be observed. NSC23766 and 2-bromopalmitate (2-BP) were used to assess the roles of Tiam1-Rac1 and palmitoylation pathways, respectively. Results: Activation of p38 MAP kinase was observed as early as 3 hours after high glucose exposure, and continued until 96 hours. Consistent with this, p38 MAP kinase activation was significantly higher in the retina from diabetic mice compared to age-matched normal mice. NSC23766 markedly attenuated hyperglycemia-induced activation of p38 MAP kinase. Lastly, 2-BP inhibited glucose-induced Rac1, Nox2 and p38 MAP kinase activation in endothelial cells. Conclusions: Tiam1-Rac1-mediated activation of Nox2 and p38 MAP kinase constitutes early signaling events leading to mitochondrial dysfunction and the development of diabetic retinopathy. Our findings also provide the first evidence to implicate novel roles for protein palmitoylation in this signaling cascade.

scholarly journals p38 MAP kinase is necessary for melanoma-mediated regulation of VE-cadherin disassembly

2010 ◽  
Vol 298 (5) ◽  
pp. C1140-C1150 ◽  
Author(s):  
Payal Khanna ◽  
Tara Yunkunis ◽  
Hari S. Muddana ◽  
Hsin Hsin Peng ◽  
Avery August ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Map Kinase ◽  
Map Kinases ◽  
Umbilical Vein ◽  
Transendothelial Migration ◽  
Melanoma Cells ◽  
P38 Map Kinase ◽  
Boyden Chamber ◽  
Gap Formation ◽  
Soluble Factors

Vascular endothelial (VE)-cadherin is localized to the endothelial borders and the adherens junctions, which are regulated by changes in mitogen-activated protein (MAP) kinases, GTPases, and intracellular calcium. We previously showed that melanoma cells induce VE-cadherin disassembly through contact with human umbilical vein endothelial cells in coculture. However, the exact mechanism by which melanoma cells signal endothelial cells to induce VE-cadherin junction disassembly is not well understood. In this study, VE-cadherin junction disassembly was further examined under fluorescence microscopy. We found that melanoma-induced VE-cadherin junction disassembly and upregulation of p38 MAP kinase in endothelial cells is regulated by both soluble factors from melanomas, particularly interleukin (IL)-8, IL-6, and IL-1β, and through vascular cell adhesion molecule-1. Neutralizing melanoma-secreted soluble factors reduced endothelial gap formation. Endothelial cells transfected with MAP kinase kinase 6, a direct activator of p38 MAP kinase, increased VE-cadherin-mediated gap formation, facilitating melanoma transendothelial migration. In contrast, endothelial cells transfected with small-interfering RNA against p38 MAP kinase expression largely prevented melanoma transendothelial migration in Boyden chamber experiments. These findings indicate that p38 MAP kinase proteins regulate VE-cadherin junction disassembly, facilitating melanoma migration across endothelial cells.

Regulation of IL-11 expression in intestinal myofibroblasts: role of c-Jun AP-1- and MAPK-dependent pathways

2003 ◽  
Vol 285 (3) ◽  
pp. G529-G538 ◽  
Author(s):  
Shigeki Bamba ◽  
Akira Andoh ◽  
Hirofumi Yasui ◽  
Jin Makino ◽  
Shokei Kim ◽  
...  
Keyword(s):  
Map Kinase ◽  
Mrna Expression ◽  
Map Kinases ◽  
Transforming Growth Factor ◽  
Intestinal Inflammation ◽  
Recombinant Adenovirus ◽  
P38 Map Kinase ◽  
Dominant Negative ◽  
Mrna Stabilization ◽  
Tgf Β1

IL-11 inhibits the activation of NF-κB and induces the Th2 polarization of CD4+T cells. The clinical utility of IL-11 is being investigated in Crohn's disease. However, physiological secretion of IL-11 in the intestine remains unclear. In this study, we investigated IL-11 secretion in human intestinal subepithelial myofibroblasts (SEMFs). Intestinal SEMFs were isolated from the human colonic mucosa. IL-11 secretion and mRNA expression were determined by ELISA and Northern blot analysis. The activating protein (AP)-1-DNA binding activity was evaluated by EMSA. IL-11 secretion was induced by IL-1β and transforming growth factor (TGF)-β1. These were also observed at the mRNA level. The EMSAs demonstrated that both IL-1β and TGF-β1 induced AP-1 activation within 2 h after stimulation, and a blockade of AP-1 activation by the recombinant adenovirus containing a dominant negative c-Jun markedly reduced the IL-1β- and TGF-β1-induced IL-11 mRNA expression. IL-1β and TGF-β1 induced an activation of ERK p42/44 and p38 MAP kinases, and the MAP kinase inhibitors (SB-202190, PD-98059, and U-0216) significantly reduced the IL-1β- and TGF-β1-induced IL-11 secretion. The upregulation of IL-11 mRNA by IL-1β- and TGF-β1 was also mediated by a p38 MAP kinase-mediated mRNA stabilization. The combination of IL-1β and TGF-β1 additively enhanced IL-11 secretion. Intestinal SEMFs secreted IL-11 in response to IL-1β- and TGF-β1. Mucosal IL-11 secretion might be important as an anti-inflammatory response in the pathogenesis of intestinal inflammation.

Extracellular Matrix Covered Biomaterials for Human Endothelial Cell Growth

1992 ◽  
Vol 15 (12) ◽  
pp. 722-726 ◽  
Author(s):  
P. Desgranges ◽  
M. Tardieu ◽  
D. Loisance ◽  
D. Barritault
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Growth ◽  
Percoll Gradient ◽  
Human Endothelial Cells ◽  
Endothelial Cell Growth ◽  
Class Ii Antigens

The aim of this study is to optimize conditions for growing endothelial cells on vascular biomaterials. Bovine cornea endothelial cells (BCEC), stimulated by basic Fibroblast Growth Factor (bFGF) secrete an extracellular matrix (ECM) similar to the Descemet membrane produced in vivo by these cells. This ECM, obtained by removing BCEC with an hypotonic shock can be used as a substratum for other endothelial cell growth. Human endothelial cells (HEC) were purified from omentum that was digested with a solution of collagenase-dispase, then filtered through nylon meshes. The cells were further purified by centrifugation onto a Percoll gradient. A comparative study on the attachment and growth of HEC on various coatings (laminin, poly-L-lysine, fibronectin or ECM) indicates that ECM is the most performing substratum. The quality of this endothelium was confirmed by the presence of factor VIII, and MHC class I and the absence of class II antigens.

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