title: 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 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.
authors.affiliation: Department of Investigative and Cardiac Biology, UW2510, GlaxoSmithKline, 709 Swedeland Rd., P.O. Box 1539, King of Prussia, PA 19406, USA.
authors.forename: Haisong
authors.initials: H
authors.lastname: Ju
authors.forename: David J
authors.initials: DJ
authors.lastname: Behm
authors.forename: Sandyha
authors.initials: S
authors.lastname: Nerurkar
authors.forename: Marianne E
authors.initials: ME
authors.lastname: Eybye
authors.forename: Robin E
authors.initials: RE
authors.lastname: Haimbach
authors.forename: Alan R
authors.initials: AR
authors.lastname: Olzinski
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Douglas
authors.forename: Robert N
authors.initials: RN
authors.lastname: Willette
mesh_terms: D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002217:Carbachol / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology*; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D018721:Muscarinic Agonists / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000235:genetics / Q000473:pathology; D013534:Survival; D013686:Telemetry; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C552886:(1,3-dihydroxyprop-2-yl)-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)imidazole; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D007093:Imidazoles; D018721:Muscarinic Agonists; D011743:Pyrimidines; C502576:SB-239063AN; D002217:Carbachol; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases