title: Chronic inhibition of p38MAPK improves cardiac and endothelial function in experimental diabetes mellitus.
abstract: To investigate the influence of p38 mitogen activated kinase (p38MAPK) on the development of diabetic cardiac and endothelial dysfunction, we assessed left ventricular and vascular function as well as inflammatory markers in diabetic rats after chronic pharmacological inhibition of p38MAPK. Diabetes mellitus was induced in rats by a single injection of streptozotocin. Rats were treated with the p38MAPK inhibitor SB 239063 (40 mg/kg/day, p.o.) or vehicle. 48 days after diabetes mellitus-induction, left ventricular function and vascular function were assessed in vivo by TIP-catheter and the autoperfused hindlimb, respectively. Cell adhesion molecules staining was quantified immunohistochemically in the heart and quadriceps muscle, respectively, as well as cardiac phosphorylation of p38MAPK by Western blot analysis. Treated and untreated diabetic groups displayed similar severe hyperglycemia. Left ventricular and endothelial function were impaired in the untreated diabetic group compared to controls (dp/dtmax: -40%, dp/dtmin: +49%, maximal vasodilatation: -57%; P < 0.05) associated with significantly increased cardiac (3-fold) and peripheral cell adhesion molecules staining, respectively. Treatment of diabetic rats with SB 239063 led to a significant reduction of diabetes-induced enhancement of p38MAPK phosphorylation associated with improved left ventricular function (dp/dtmax: +39%, dp/dtmin: +47%; P < 0.05) and peripheral endothelial function (maximal vasodilatation: +71%; P < 0.05) under diabetic conditions. This was associated with reduced cardiac and peripheral inflammation indexed by reduced adhesion molecules content. Pharmacological inhibition of p38MAPK is sufficient to mitigate the development of diabetic cardiac and endothelial dysfunction despite of hyperglycemia. Our data suggest that the anti-inflammatory properties due to p38MAPK inhibition contribute to these beneficial cardiovascular effects.
authors.affiliation: Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Riad
authors.forename: Daniel
authors.initials: D
authors.lastname: Unger
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
authors.forename: Zarah
authors.initials: Z
authors.lastname: Mohr
authors.forename: Meike
authors.initials: M
authors.lastname: Sobirey
authors.forename: Marc
authors.initials: M
authors.lastname: Dorenkamp
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008297:Male; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D016277:Ventricular Function, Left / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D018799:Intercellular Adhesion Molecule-1; D013311:Streptozocin; D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063