Blockade of VEGF-induced GSK/β-catenin signaling, uPAR expression and increased permeability by dominant negative p38α.

Experimental Eye Research
Jinling YangM Ali Behzadian

Abstract

The goal of this study was to define the role of p38alpha MAP kinase in VEGF-induced vascular permeability increase. Activation of p38 is correlated with increased permeability in endothelial cells treated with VEGF or high glucose and in retinas of diabetic animal models. We have shown previously that p38 inhibitors preserve endothelial barrier function and block VEGF-induced GSK/beta-catenin signaling. Here, we present data demonstrating that adenoviral vector delivery of a dominant negative p38alpha mutant blocks this signaling pathway and preserves barrier function. This p38alpha mutant was altered on its ATP-binding site, which eliminates its kinase activity. Bovine retinal endothelial (BRE) cells were transduced with recombinant adenovirus containing the p38alpha mutants or empty vector. Successful transduction was confirmed by expression of GFP and p38 increase. Blockade of p38 activity by p38alpha mutant was demonstrated by inhibition of VEGF-induced phosphorylation of a p38 target, MAP kinase activated protein kinase 2 (MK-2). The mutant also prevented VEGF-induced GSK phosphorylation and beta-catenin cytosolic accumulation and nuclear translocation as shown by cell fractionation and Western blotting. Quantitative real...Continue Reading

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Citations

Feb 19, 2013·Journal of Cellular and Molecular Medicine·Xiaoren TangSalomon Amar
Feb 2, 2021·European Journal of Medicinal Chemistry·Moustafa M MadkourMohammed I El-Gamal

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