Document Detail

Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus.
MedLine Citation:
PMID:  16937126     Owner:  NLM     Status:  MEDLINE    
AIMS/HYPOTHESIS: We investigated the effect of SB 203580, a pharmacological inhibitor of p38 mitogen-activated protein kinase (MAPK), on cardiac inflammation, cardiac fibrosis, and left ventricular function using an animal model of diabetic cardiomyopathy. MATERIALS AND METHODS: Diabetes mellitus was induced by streptozotocin (50 mg/kg i.p. for 5 days) in 20 C57/BL6J mice. Diabetic mice were treated daily with the p38 MAPK inhibitor SB 203580 (1 mg/kg daily, n=10) or with placebo (n=10) and were compared to non-diabetic controls. Left ventricular function was measured by pressure-volume loops after 8 weeks of diabetes mellitus. The parameters for systolic function were the end systolic pressure-volume relationship (ESPVR) and the left ventricular end systolic pressure. The parameters for diastolic function were the left ventricular end diastolic pressure and the end diastolic pressure-volume relationship (EDPVR). Cardiac tissue was analysed by ELISA for the protein content of the cytokines TNF-alpha, IL6, IL1-beta, and TGF-beta1. Phosphorylation of MAPK p38 was analysed by western blot, and the total cardiac collagen content was analysed by Sirius red staining. RESULTS: Left ventricular dysfunction was documented by impaired ESPVR and EDPVR. Cardiac cytokine levels and cardiac fibrosis were increased in diabetic animals compared to controls. Treatment with the p38 inhibitor normalised cardiac cytokine levels and improved systolic function, but did not change cardiac fibrosis and diastolic dysfunction compared to placebo. CONCLUSIONS/INTERPRETATION: Pharmacological inhibition of p38 MAPK prevents cardiac inflammation and attenuates left ventricular dysfunction in diabetic cardiomyopathy.
D Westermann; S Rutschow; S Van Linthout; A Linderer; C Bücker-Gärtner; M Sobirey; A Riad; M Pauschinger; H-P Schultheiss; C Tschöpe
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-08-26
Journal Detail:
Title:  Diabetologia     Volume:  49     ISSN:  0012-186X     ISO Abbreviation:  Diabetologia     Publication Date:  2006 Oct 
Date Detail:
Created Date:  2006-09-06     Completed Date:  2007-03-26     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0006777     Medline TA:  Diabetologia     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  2507-13     Citation Subset:  IM    
Department of Cardiology and Pneumology, Charité University Hospital, Benjamin Franklin Campus, Berlin, Germany.
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MeSH Terms
Body Weight
Cytokines / metabolism*
Diabetes Mellitus, Experimental / enzymology,  physiopathology*
Diabetic Angiopathies / physiopathology,  prevention & control
Enzyme Inhibitors / therapeutic use
Heart / anatomy & histology,  physiopathology*
Imidazoles / therapeutic use
Inflammation / physiopathology
Mice, Inbred C57BL
Organ Size
Pyridines / therapeutic use
Systole / physiology
Ventricular Dysfunction, Left / physiopathology*,  prevention & control
Ventricular Function, Left
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors,  metabolism*
Reg. No./Substance:
0/Cytokines; 0/Enzyme Inhibitors; 0/Imidazoles; 0/Pyridines; 0/SB 203580; EC Mitogen-Activated Protein Kinases

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