Received for publication July 23, 2003.
Revised September 7, 2003.
Accepted for publication September 16, 2003.

p38 MAPK Inhibitors Ameliorate Target Organ Damage in Hypertension: Part 1, p38 MAPK-Dependent Endothelial Dysfunction and Hypertension

Abstract

Numerous mediators, believed to play a role in endothelial dysfunction (e.g. neurohormones, cytokines, hypoxia and stretch), have been shown to activate p38 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), TNF- and LPS increased phosphorylation of p38 MAPK (P-p38 MAPK) and increased ICAM-1 expression. Preincubation with highly selective p38 MAPK inhibitors, SB-281832 or SB-239063, dose-dependently reduced ICAM-1 expression in HUVECs. In stroke-prone spontaneously hypertensive rats (SHRSP), 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 SHRSP strain induced endothelial dysfunction (ex vivo vascular reactivity analysis), microalbuminuria and an increase in blood pressure within 4 weeks. Chronic dietary dosing (approx. 100mg/kg/day) with SB-281832 inhibited the SFD diet- induced hypertension. In addition, delayed treatment also significantly improved survival and restored NO- mediated endothelium-dependent relaxation in SFD-SHRSPs 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.

Key words: adhesion molecules, endothelial dysfunction, hypertension, p38 MAPK, salt-sensitivity, signal transduction

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