Intervention Of Flavones For Cardiovascular Alterations In Experimental Diabetes

Background:Diabetes is usually associated with cardiovascular complications which are the principal cause of diabetic mortality. Oxidative stress induced by hyperglycemia and vascular endothelium dysfunction appear in the early duration of diabetes, which plays a pivotally initial role in the development of diabetic cardiovascular complications. The total flavonoids of Flos Chrysanthemi (TF) and its bioactive components, luteolin and apigenin, exert vasorelaxation, anti-arrhythmia, anti-cardiac and cerebral ischamia/reperfusion injuries, anti-oxidative stress in many kinds of experimental models. However, it remains unknown whether TF and its components, luteolin and apigenin, have beneficial effects on diabetic cardiowascular system. Objective:To explore the intervening effects of TF, luteolin and apigenin on experimental diabetic cardiovascular alterations and its underlying mechanisms. Methods:Cardiovascular and anti-oxidative effects of TF (200 mg/kg, i.g.), luteolin (10,50,100 mg/kg, i.g.) and apigenin (10,50,100 mg/kg, i.g.) for 8 weeks on experimental diabetic rat model induced by streptozotocin (60 mg/kg, i.p.) were assayed. Endothelium-dependent vasorelaxation of luteolin (5.74μM) and apigenin (5.00μM) on high glucose (44 mM,4 h) perfused thoracic aortas were also measured. Moreover, the cell viability, reactive oxygen species (ROS) production, and protein kinase Cβ2 (PKCβ2) expression in high glucose (33 mM,48 h) cultured human umbilical vein endothelial cells (HUVEC) treated with luteolin and apigenin were detected. Results:Treatment with TF, luteolin and apigenin did not reduced the blood glucose level in diabetic rats, but markedly improved the body weight dose dependently. In diabetic hearts, ROS production, myocardial fibrosis, ventricular hypertrophy and the opening of cardiac mitochondrial permeability transition pore induced by Ca2+were reduced, the activity of superoxide dismutase (SOD) and left ventricular systolic/diastolic functions were enhanced by TF, luteolin and apigenin. In diabetic aortas, ROS level and PMA-induced vasocontraction were inhibited, and endothelial nitric oxide synthase (eNOS) activity, nitric oxide (NO) level, and endothelium-dependent vasorelaxation were improved by TF, luteolin and apigenin. Such vasorelaxation effect of TF, luteolin and apigenin was canceled by L-NAME and methylene blue. There was no difference between TF, luteolin and apigenin treated diabetic rats. Luteolin and apigenin markedly relaxed endothelium-intact aortas, which was reduced by functional removal of endothelium. Acute treatment with luteolin and apigenin inhibited the impairment of endothelium-dependent vasorelaxation (which was canceled by L-NAME) and ROS production, enhanced NO level and the activities of SOD and eNOS in high glucose perfused aortas. In high glucose cultured HUVEC, the cell viability was improved, the ROS production and membrane PKCβ2 expression. Conclusions:The results indicate that oral administration of TF might exert the cardiovascular protection by its two main bioactive components, apigenin and luteolin. Enhancing SOD activity and reducing ROS production in cardiovascular system blunted cardiac MPTP opening and activated aortic eNOS-NO-cGMP pathway, which mediated the cardiovascular effects of by luteolin and apigenin in high glucose injured or diabetic rats. It is noticeable that inhibiting the membrane PKCβ2 expression and/or translocation from the cytosol to the cytomembrane in endothelial cells, and reducing oxidative stress were vital to reducing diabetic cardiovascular injuries by luteolin and apigenin.