Oral treatment with a zinc complex of acetylsalicylic acid prevents diabetic cardiomyopathy in a rat model of type-2 diabetes: activation of the Akt pathway

摘要

Background Type-2 diabetics have an increased risk of cardiomyopathy, and heart failure is a major cause of death among these patients. Growing evidence indicates that proinflammatory cytokines may induce the development of insulin resistance, and that anti-inflammatory medications may reverse this process. We investigated the effects of the oral administration of zinc and acetylsalicylic acid, in the form of bis(aspirinato)zinc(II)-complex Zn(ASA)₂, on different aspects of cardiac damage in Zucker diabetic fatty (ZDF) rats, an experimental model of type-2 diabetic cardiomyopathy. Methods Nondiabetic control (ZL) and ZDF rats were treated orally with vehicle or Zn(ASA)₂ for 24?days. At the age of 29–30?weeks, the electrical activities, left-ventricular functional parameters and left-ventricular wall thicknesses were assessed. Nitrotyrosine immunohistochemistry, TUNEL-assay, and hematoxylin-eosin staining were performed. The protein expression of the insulin-receptor and PI3K/AKT pathway were quantified by Western blot. Results Zn(ASA)₂-treatment significantly decreased plasma glucose concentration in ZDF rats (39.0?±?3.6 vs 49.4?±?2.8?mM, P?2 normalized the increased left-ventricular diastolic stiffness (end-diastolic pressure–volume relationship: 0.064?±?0.008 vs 0.084?±?0.014?mmHg/μl; end-diastolic pressure: 6.5?±?0.6 vs 7.9?±?0.7?mmHg, P?2. Left-ventricular wall thickness, assessed by echocardiography, did not differ among the groups. However histological examination revealed an increase in the cardiomyocytes’ transverse cross-section area in ZDF compared to the ZL rats, which was significantly decreased after Zn(ASA)₂-treatment. Additionally, a significant fibrotic remodeling was observed in the diabetic rats compared to ZL rats, and Zn(ASA)₂-administered ZDF rats showed a similar collagen content as ZL animals. In diabetic hearts Zn(ASA)₂ significantly decreased DNA-fragmentation, and nitro-oxidative stress, and up-regulated myocardial phosphorylated-AKT/AKT protein expression. Zn(ASA)₂ reduced cardiomyocyte death in a cellular model of oxidative stress. Zn(ASA)₂ had no effects on altered myocardial CD36, GLUT-4, and PI3K protein expression. Conclusions We demonstrated that treatment of type-2 diabetic rats with Zn(ASA)₂ reduced plasma glucose-levels and prevented diabetic cardiomyopathy. The increased myocardial AKT activation could, in part, help to explain the cardioprotective effects of Zn(ASA)₂. The oral administration of Zn(ASA)₂ may have therapeutic potential, aiming to prevent/treat cardiac complications in type-2 diabetic patients.