Abstract 9378: Glucose Fluctuations Aggravate the Vulnerability of Diabetic Heart Against Ischemia/reperfusion Mediated via microRNAs Modulation

Abstract

[Objective] Frequent hypoglycemia attack reportedly increased cardiovascular events and mortality in patients with diabetes mellitus (DM). In the present study, we investigated whether glucose fluctuations may increase the susceptibility to ischemia/reperfusion in diabetic rat heart and the involvement of microRNA (miRNA) as well. [Methods and Results] In in vitro experiments, cultured cardiomyocytes were alternately exposed to high (450 mg/dL) and low (30 mg/dL) concentrations of glucose for 5 days. Exposure to glucose fluctuations increased level of reactive oxygen species (ROS) and made cardiomyocytes more vulnerable to oxidative stress compared to sustained high glucose exposure. In in vivo experiments, rats were divided into 3 groups: control, DM, and DM with glucose fluctuations. DM was induced by intravenous injection of streptozotocin (60 mg/kg) and glucose fluctuation was induced by 24h-fasting and insulin injection (0.5 IU/kg). Isolated hearts were subjected to 20min global ischemia followed by 30min reperfusion. The infarct size was larger in diabetic hearts with glucose fluctuations than those with consecutive hyperglycemia. Electron microscopy disclosed that mitochondria were swollen and structure of cristae was destroyed in diabetic heart, and those changes were aggravated by glucose fluctuations. The level of ROS and activities of intracellular antioxidant enzymes were analyzed in search of possible mechanisms. Level of ROS was increased, and activities of catalase and superoxide dismutase were down-regulated in the heart with glucose fluctuations compared to sustained hyperglycemia. Further, microarray analysis was performed to explore the expression profiles of miRNAs in each group. Expressions of mir-200c and -141 were more abundant in the hearts exposed to glucose fluctuations than those with sustained high glucose level. We also confirmed that these miRNAs seem to contribute to the decreased activities of antioxidant enzymes and subsequent ROS increase. [Conclusions] Glucose fluctuations increased ROS level and enhanced ischemia/reperfusion injury in diabetic heart. Up-regulations of mir-200c and -141 may account for ROS increase by suppressing antioxidant enzymes.