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

TLDR

Numerous mediators implicated in endothelial dysfunction, such as neurohormones, cytokines, hypoxia, and stretch, activate p38 MAPK across various cell types. The study aimed to investigate how p38 MAPK is regulated in endothelium and its contribution to endothelial dysfunction and salt sensitivity. The authors chronically dosed spontaneously hypertensive‑stroke prone rats with the selective p38 MAPK inhibitor SB‑239063AN (≈100 mg kg⁻¹ day⁻¹) to assess its effect on salt/fat‑diet‑induced hypertension. Treatment of HUVECs with TNF‑α or LPS increased p38 phosphorylation and ICAM‑1 expression, while selective p38 inhibitors dose‑dependently reduced ICAM‑1; in SHR‑SP rats, SFD induced endothelial dysfunction, albuminuria, and hypertension, all of which were prevented or reversed by chronic or delayed SB‑239063AN administration, demonstrating a causal role for p38 MAPK in endothelial inflammation and salt‑induced 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 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.