Cardioprotective and anti-inflammatory effects of interleukin converting enzyme inhibition in experimental diabetic cardiomyopathy.
OBJECTIVE
We investigated the effect of pharmacological inhibition of the interleukin converting enzyme (ICE) on cardiac inflammation, apoptosis, fibrosis, and left ventricular function in an animal model of diabetes.


METHODS
Diabetes was induced in 24 Sprague-Dawley rats by injection of streptozotozin (STZ) (70 mg/kg). Diabetic animals were treated with the interleukin converting enzyme (ICE) inhibitor (ICEI) (n = 12) or with a placebo (n = 12). Nondiabetic rats served as controls (n = 12). Left ventricular function was documented 6 weeks after induction of diabetes. Cardiac tissue was analyzed for the expression of cytokines, intracellular adhesion molecule-1 and vascular cell adhesion molecule-1, leukocyte and macrophage integrins, and collagen. Phosphorylation of Akt was analyzed by Western blot and apoptosis by Blc-2 and Bax measurements.


RESULTS
Left ventricular function was significantly impaired in diabetic animals. This was accompanied by a significant increase of cytokines, cell adhesion molecules, leukocytes and macrophages, and collagen content. In addition, the phosphorylation state of Akt was reduced. These changes were significantly attenuated in the diabetic group treated with ICEI.


CONCLUSIONS
Cardiac dysfunction is associated with cardiac inflammation in experimental diabetic cardiomyopathy. Both of these--cardiac dysfunction and inflammation--are attenuated after treatment with ICEI. These data suggest that anticytokine-based therapies might be beneficial in diabetic cardiomyopathy.
Westermann
Dirk
D
Department of Cardiology, Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany.
Van Linthout
Sophie
S
Dhayat
Sameer
S
Dhayat
Nasser
N
Escher
Felicitas
F
Bücker-Gärtner
Carola
C
Spillmann
Frank
F
Noutsias
Michel
M
Riad
Alexander
A
Schultheiss
Heinz-Peter
HP
Tschöpe
Carsten
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000276:immunology*; D020170:Caspase 1 / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications*; D004195:Disease Models, Animal; D005355:Fibrosis; D006321:Heart / Q000187:drug effects*; D007249:Inflammation; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left / Q000187:drug effects
D020170:Caspase 1