Cardioprotective and Anti-Inflammatory Effects of Interleukin Converting Enzyme Inhibition in Experimental Diabetic Cardiomyopathy

Cardioprotective and Anti-Inflammatory Effects of Interleukin Converting Enzyme Inhibition in Experimental Diabetic Cardiomyopathy Dirk Westermann , Sophie Van Linthout , Sameer Dhayat , Nasser Dhayat , Felicitas Escher , Carola Bücker-Gärtner , Frank Spillmann , Michel Noutsias , Alexander Riad , Heinz-Peter Schultheiss and Carsten Tschöpe From the Department of Cardiology and Pneumology, Charité, Universititätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany Address correspondence and reprint requests to Carsten Tschöpe, MD, Department of Cardiology, Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany. E-mail: carsten.tschoepe{at}yahoo.com Abstract 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. RESEARCH DESIGN AND 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. CAM, cell adhesion molecule ICAM, intracellular adhesion molecule ICE, interleukin converting enzyme ICEI, ICE inhibitor IFN, interferon IL, interleukin LVEDP, left ventricular end diastolic pressure LVP, left ventricular press