title: Hypertensive end-organ damage and premature mortality are p38 mitogen-activated protein kinase-dependent in a rat model of cardiac hypertrophy and dysfunction.
abstract: BACKGROUND
  Numerous pathological mediators of cardiac hypertrophy (eg, neurohormones, cytokines, and stretch) have been shown to activate p38 MAPK. The purpose of the present study was to examine p38 MAPK activation and the effects of its long-term inhibition in a model of hypertensive cardiac hypertrophy/dysfunction and end-organ damage.
  
  
  RESULTS
  In spontaneously hypertensive stroke-prone (SP) rats receiving a high-salt/high-fat diet (SFD), myocardial p38 MAPK was activated persistently during the development of cardiac hypertrophy and inactivated during decompensation. Long-term oral treatment of SFD-SP rats with a selective p38 MAPK inhibitor (SB239063) significantly enhanced survival over an 18-week period compared with the untreated group (100% versus 50%). Periodic echocardiographic analysis revealed a significant reduction in LV hypertrophy and dysfunction in the SB239063-treatment groups. Little or no difference in blood pressure was noted in the treatment or vehicle groups. Basal and stimulated (lipopolysaccharide) plasma tumor necrosis factor-alpha concentrations were reduced in the SB239063-treatment groups. In vitro vasoreactivity studies demonstrated a significant preservation of endothelium-dependent relaxation in animals treated with the p38 MAPK inhibitor without effects on contraction or NO-mediated vasorelaxation. Proteinuria and the incidence of stroke (53% versus 7%) were also reduced significantly in the SB239063-treated groups.
  
  
  CONCLUSIONS
  These results demonstrate a crucial role for p38 MAPK in hypertensive cardiac hypertrophy and end-organ damage. Interrupting its function with a specific p38 MAPK inhibitor halts clinical deterioration.
authors.affiliation: Cardiovascular Pharmacology, GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Behr
authors.forename: S S
authors.initials: SS
authors.lastname: Nerurkar
authors.forename: A H
authors.initials: AH
authors.lastname: Nelson
authors.forename: R W
authors.initials: RW
authors.lastname: Coatney
authors.forename: T N
authors.initials: TN
authors.lastname: Woods
authors.forename: A
authors.initials: A
authors.lastname: Sulpizio
authors.forename: S
authors.initials: S
authors.lastname: Chandra
authors.forename: D P
authors.initials: DP
authors.lastname: Brooks
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.forename: J C
authors.initials: JC
authors.lastname: Lee
authors.forename: E H
authors.initials: EH
authors.lastname: Ohlstein
authors.forename: C E
authors.initials: CE
authors.lastname: Angermann
authors.forename: J L
authors.initials: JL
authors.lastname: Adams
authors.forename: J
authors.initials: J
authors.lastname: Sisko
authors.forename: J D
authors.initials: JD
authors.lastname: Sackner-Bernstein
authors.forename: R N
authors.initials: RN
authors.lastname: Willette
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000401:mortality / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D004789:Enzyme Activation; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011507:Proteinuria / Q000517:prevention & control / Q000652:urine; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020521:Stroke / Q000473:pathology / Q000517:prevention & control; D015996:Survival Rate; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D007093:Imidazoles; D008070:Lipopolysaccharides; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063