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Research ArticleCARDIOVASCULAR

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

Haisong Ju, David J. Behm, Sandyha Nerurkar, Marianne E. Eybye, Robin E. Haimbach, Alan R. Olzinski, Stephen A. Douglas and Robert N. Willette
Journal of Pharmacology and Experimental Therapeutics December 2003, 307 (3) 932-938; DOI: https://doi.org/10.1124/jpet.103.057422
Haisong Ju
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David J. Behm
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Sandyha Nerurkar
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Marianne E. Eybye
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Robin E. Haimbach
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Alan R. Olzinski
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Stephen A. Douglas
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Robert N. Willette
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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-α 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.

Footnotes

  • DOI: 10.1124/jpet.103.057422.

  • ABBREVIATIONS: HUVEC, human umbilical vein endothelial cell; SHR-SP, spontaneously hypertensive-stroke prone; TNF, tumor necrosis factor; MAPK, mitogen-activated protein kinase; LPS, lipopolysaccharide; ICAM-1, intercellular adhesion molecule-1; PECAM-1, platelet-endothelial cell adhesion molecule-1; WKY, Wistar-Kyoto; SD, Sprague-Dawley; SFD, salt/fat diet; ND, normal chow diet; SNP, sodium nitroprusside; P-p38, phospho-p38; MAP, mean arterial pressure; BP, blood pressure; NO, nitric oxide; ROS, reactive oxygen species.

  • ↵1 These authors contributed equally to this study.

    • Received July 22, 2003.
    • Accepted September 16, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 307 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 307, Issue 3
1 Dec 2003
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Research ArticleCARDIOVASCULAR

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

Haisong Ju, David J. Behm, Sandyha Nerurkar, Marianne E. Eybye, Robin E. Haimbach, Alan R. Olzinski, Stephen A. Douglas and Robert N. Willette
Journal of Pharmacology and Experimental Therapeutics December 1, 2003, 307 (3) 932-938; DOI: https://doi.org/10.1124/jpet.103.057422

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Research ArticleCARDIOVASCULAR

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

Haisong Ju, David J. Behm, Sandyha Nerurkar, Marianne E. Eybye, Robin E. Haimbach, Alan R. Olzinski, Stephen A. Douglas and Robert N. Willette
Journal of Pharmacology and Experimental Therapeutics December 1, 2003, 307 (3) 932-938; DOI: https://doi.org/10.1124/jpet.103.057422
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