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

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 ϭ 12) or with a placebo (n ϭ 12). Nondiabetic rats served as controls (n ϭ 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.

Therapeutic Potential of HDL in Cardioprotection and Tissue Repair

“…In agreement with the direct anti-inflammatory properties of HDL (Cockerill et al 2001;Hyka et al 2001), apo A-I transfer decreased the diabetes-induced intramyocardial inflammation (Westermann et al 2007b, c) as indicated by the reduction in ICAM-1, vascular cell adhesion molecule (VCAM)-1, and TNF-α mRNA expression ) and VCAM-1 protein expression (Van Linthout et al 2010b). Downregulation of VCAM-1/ICAM-1 expression suppresses monocyte-endothelial cell adhesion and subsequent transendothelial migration of inflammatory cells.…”

Cardiac Inflammation Contributes to Changes in the Extracellular Matrix in Patients With Heart Failure and Normal Ejection Fraction

“…Recently, it was shown that immunocompetent cells like T-cells (CD3 ϩ ) can indeed alter tissue remodelling in vitro, 45 and we have shown that cardiac inflammation is associated with excessive collagen accumulation in experimental diabetic cardiomyopathy in 1 animal model of HFNEF. 25 There is experimental and clinical evidence that inflammatory cells might modulate cardiac function in HF with reduced 46,47 and normal 48,49 EF. The direct effects of these cells are still under debate, but it has been suggested that increased inflammation is associated with the development of systolic HF by distinct changes in the ratio of MMP to TIMP.…”

Chronic Heart Failure and Inflammation

“…[122][123][124][125] Cardiac inflammation and leukocyte recruitment, as observed in the setting of diabetic cardiomyopathy, seems to be mediated in part through the NLRP3 inflammasome in a similar fashion to MI. 68,[126][127][128][129][130] It has been hypothesized that the mechanism of inflammasome activation in diabetic cardiomyopathy is dependent on the combination of oxidative stress and reactive oxygen species production, as a result of mitochondrial dysfunction. 131,132 Damaged mitochondria are removed from the cell in a process known as mitophagy, and if this system is overwhelmed or ineffective, increased reactive oxygen species ensues.…”