Numerous mediators, believed to play a role in endothelial dysfunction (e.g.,
neurohormones,
cytokines,
hypoxia, and stretch), have been shown to activate
p38 mitogen-activated protein kinase (MAPK) in a variety of cell types. The purpose of the present study was to examine the regulation of
p38 MAPK in endothelium and its role in endothelial dysfunction and
salt sensitivity. In cultured human umbilical vein endothelial cells (HUVECs),
tumor necrosis factor-alpha and
lipopolysaccharide increased phosphorylation of
p38 MAPK (P-p38 MAPK) and increased
ICAM-1 expression. Preincubation with highly selective
p38 MAPK inhibitors, 1-(1,3-dihydroxyprop-2-yl)-4-(4-fluorophenyl)-5-[2-phenoxypyrimidin-4-yl]
imidazole (SB-239063AN) or
SB-239063, dose dependently reduced
intercellular adhesion molecule-1 expression in HUVECs. In spontaneously hypertensive-
stroke prone rats (SHR-SP), P-p38 MAPK was localized by immunohistochemistry to the aortic endothelium and adventitia but was undetectable in aortae from normotensive rats. Introduction of a
salt/fat diet (SFD) to the SHR-SP strain induced endothelial dysfunction (ex vivo vascular reactivity analysis),
albuminuria, and an increase in blood pressure within 4 weeks. Chronic dietary dosing (approx. 100 mg/kg/day) with
SB-239063AN inhibited the SFD diet-induced
hypertension. In addition,
delayed treatment also significantly improved survival and restored
nitric oxide-mediated endothelium-dependent relaxation in SFD-SHR-SPs with established endothelial dysfunction. These results suggest an important role for
p38 MAPK in endothelial
inflammation and dysfunction as well as providing the first evidence for
p38 MAPK-dependent
hypertension.