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

McGinn, S, Saad, S, Poronnik, P and Pollock, C 2003, 'High glucose-mediated effects on endothelial cell proliferation occur via p38 MAP kinase', American Journal of Physiology: Endocrinology and Metabolism, vol. 285, no. 4, pp. 708-717.


Document type: Journal Article
Collection: Journal Articles

Title High glucose-mediated effects on endothelial cell proliferation occur via p38 MAP kinase
Author(s) McGinn, S
Saad, S
Poronnik, P
Pollock, C
Year 2003
Journal name American Journal of Physiology: Endocrinology and Metabolism
Volume number 285
Issue number 4
Start page 708
End page 717
Total pages 10
Publisher American Physiological Society
Abstract 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)-beta1 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-beta1 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-beta1. 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.
Subject Cell Physiology
Keyword(s) endothelial cell
growth
high glucose
p38 mitogen-activated protein kinase
p42/44 mitogen-activated protein kinase
transforming growth factor-ß1
ISSN 0193-1849
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