p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage

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Item Type:	Article
Title:	p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage
Creators Name:	Park, J.K., Fischer, R., Dechend, R., Shagdarsuren, E., Gapeljuk, A., Wellner, M., Meiners, S., Gratze, P., Al-Saadi, N., Feldt, S., Fiebeler, A., Madwed, J.B., Schirdewan, A., Haller, H., Luft, F.C. and Mueller, D.N.
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.
Keywords:	Angiotensin II, p38, Electrical remodeling, Cardiac and renal damage, Animals, Rats
Source:	Hypertension
ISSN:	0194-911X
Publisher:	American Heart Association
Volume:	49
Number:	3
Page Range:	481-489
Date:	March 2007
Official Publication:	https://doi.org/10.1161/01.HYP.0000256831.33459.ea
PubMed:	View item in PubMed

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