title: p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage.
abstract: We investigated whether or not p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage. We used double transgenic rats harboring both human renin and angiotensinogen genes (dTGRs). dTGR, with or without p38 inhibitor (BIRB796; 30 mg/kg per day in the diet), and nontransgenic Sprague-Dawley rats were studied in 2 protocols. In protocol 1 (week 7), systolic blood pressure of untreated dTGRs was 204+/-4 mm Hg, but partially reduced after BIRB796 treatment (166+/-7 mm Hg), whereas Sprague-Dawley rats were normotensive. The cardiac hypertrophy index was unchanged in untreated and BIRB796-treated dTGRs. The beta-myosin heavy chain expression of BIRB796-treated hearts was significantly lower in BIRB796 compared with dTGRs, indicating a delayed switch to the fetal isoform. BIRB796 treatment significantly reduced cardiac fibrosis, connective tissue growth factor, tumor necrosis factor-alpha, interleukin-6, and macrophage infiltration. Albuminuria was not reduced in BIRB796-treated dTGRs. Tubular and glomerular damage with tumor necrosis factor-alpha expression was unaltered, although serum creatinine and cystatin C were normalized. Renal macrophage infiltration, fibrosis, and vessel damage were reduced. In protocol 2 (week 8), we focused on mortality and arrhythmogenic electrical remodeling. Mortality of untreated dTGRs was 100% but was reduced to 10% in the BIRB796 group. Cardiac magnetic field mapping showed prolongation of depolarization and repolarization in untreated dTGRs compared with Sprague-Dawley rats with a partial reduction by BIRB796. Programmed electrical stimulation elicited ventricular tachycardias in 81% of untreated dTGRs but only in 48% of BIRB796-treated dTGRs. In conclusion, BIRB796 improved survival, target organ damage, and arrhythmogenic potential in angiotensin II-induced target organ damage.
authors.affiliation: Medical Faculty of the Charité, Franz Volhard Clinic, HELIOS Klinikum, Berlin, Germany.
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.forename: Robert
authors.initials: R
authors.lastname: Fischer
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
authors.forename: Erdenechimeg
authors.initials: E
authors.lastname: Shagdarsuren
authors.forename: Andrej
authors.initials: A
authors.lastname: Gapeljuk
authors.forename: Maren
authors.initials: M
authors.lastname: Wellner
authors.forename: Silke
authors.initials: S
authors.lastname: Meiners
authors.forename: Petra
authors.initials: P
authors.lastname: Gratze
authors.forename: Nidal
authors.initials: N
authors.lastname: Al-Saadi
authors.forename: Sandra
authors.initials: S
authors.lastname: Feldt
authors.forename: Anette
authors.initials: A
authors.lastname: Fiebeler
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Madwed
authors.forename: Alexander
authors.initials: A
authors.lastname: Schirdewan
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Muller
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D002318:Cardiovascular Diseases / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D007674:Kidney Diseases / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D009281:Naphthalenes / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D010671:Phenylurea Compounds
chemical_list: D000804:Angiotensin II; D000808:Angiotensinogen; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D012083:Renin; D048051:p38 Mitogen-Activated Protein Kinases; C452139:doramapimod; D010671:Phenylurea Compounds