p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage.
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.
Park
Joon-Keun
JK
Medical Faculty of the Charité, Franz Volhard Clinic, HELIOS Klinikum, Berlin, Germany.
Fischer
Robert
R
Dechend
Ralf
R
Shagdarsuren
Erdenechimeg
E
Gapeljuk
Andrej
A
Wellner
Maren
M
Meiners
Silke
S
Gratze
Petra
P
Al-Saadi
Nidal
N
Feldt
Sandra
S
Fiebeler
Anette
A
Madwed
Jeffrey B
JB
Schirdewan
Alexander
A
Haller
Hermann
H
Luft
Friedrich C
FC
Muller
Dominik N
DN
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
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