Pharmacologically activated migration of aortic endothelial cells is mediated through p38 SAPK.
Impairment in endothelial cell (EC) function plays a central role in vascular diseases (e.g. atherosclerosis, restenosis, diabetic angiopathies, microvascular angina, peripheral arterial disease). BRX-235 (a novel small molecule synthesized by Biorex, Hungary) has a potent vasculoprotective activity in different in vivo and in vitro studies. Since the importance of the p38 pathway in EC homeostasis and migration in particular is well documented, we have carried out studies to address the role of the p38 stress activated protein kinase (p38 SAPK) in the mode of action of BRX-235. In this study, Bovine aortic endothelial cells were used in a wounding migration assay (WMA) and for Western-blot analysis to study the effect and molecular mechanism of BRX-235-induced EC migration. The bovine aortic endothelial (BAE) cells were shown to be good models for EC migration. Both endothelial cell growth factor (ECGF)- and BRX-235-induced BAE cell migration were shown to be inhibited by SB 203580, a specific inhibitor of p38 SAPK. It was also shown that, BRX-235 induces phosphorylation of p38 SAPK without affecting p38 SAPK protein levels. Thus, BRX-235 acts upstream of p38 SAPK. In summary, we have shown that p38 SAPK is a potential pharmacological mediator for candidate drugs that target the endothelium.
Dénes
László
L
Biorex Research and Development Company, H-8201 Veszprém, P.O.B. 12, Hungary. laszlo.denes@biorex.hu
Jednákovits
Andrea
A
Hargitai
Judit
J
Pénzes
Zoltán
Z
Balla
András
A
Tálosi
László
L
Krajcsi
Péter
P
Csermely
Péter
P
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000201:enzymology; D015153:Blotting, Western; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects*; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors; D004727:Endothelium / Q000166:cytology* / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010078:Oxazines / Q000494:pharmacology*; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010078:Oxazines; D010880:Piperidines; D011725:Pyridines; C469852:iroxanadine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580