Satoru Nishio

Glucose fluctuations increase the incidence of atrial fibrillation in diabetic rats.

AIMS We investigated whether glucose fluctuations aggravate cardiac fibrosis and increase the occurrence of atrial fibrillation (AF) in rats with diabetes mellitus (DM). METHODS AND RESULTS Streptozotocin-induced diabetic rats were randomly divided into three groups: uncontrolled DM (U-STZ) group, controlled DM (C-STZ) group, and DM with glucose fluctuations (STZ-GF) group. Glucose fluctuations were induced by fasting for 24 h and additional regular insulin injections (0.5 IU/kg) administered three times per week for three consecutive weeks. C-STZ rats were administered long acting insulin (20 IU/kg) twice a day to control blood glucose levels. Cardiac fibrosis evaluated by Masson trichrome staining and the expressions of collagen type 1, collagen type 3, and α-smooth muscle actin were increased in U-STZ rats compared with C-STZ rats, which were more pronounced in STZ-GF rats. The inducibility of AF was significantly larger in U-STZ rats than C-STZ rats and was greatest in STZ-GF rats. To explore the mechanism of cardiac fibrosis, we investigated the levels of reactive oxygen species (ROS) and apoptosis. The expression of malondialdehyde, an indicator of ROS levels, was significantly upregulated in STZ-GF rats compared with U-STZ rats, along with increased thioredoxin-interacting protein (Txnip) expression in STZ-GF rats. Furthermore, caspase-3 expression and the number of TUNEL-positive cells were significantly increased in STZ-GF rats compared with U-STZ and C-STZ rats. CONCLUSION Glucose fluctuations increase the incidence of AF by promoting cardiac fibrosis. Increased ROS levels caused by upregulation of Txnip expression may be a mechanism whereby in glucose fluctuations induce fibrosis.

Inhibition of Na+‐H+ exchange as a mechanism of rapid cardioprotection by resveratrol

BACKGROUND AND PURPOSE Resveratrol is a polyphenol abundantly found in grape skin and red wine. In the present study, we investigated whether resveratrol exerts protective effects against cardiac ischaemia/reperfusion and also explored its mechanisms.

Glucose Fluctuations Aggravate Cardiac Susceptibility to Ischemia/Reperfusion Injury by Modulating MicroRNAs Expression.

BACKGROUND The influence of glucose fluctuations (GF) on cardiovascular complications of diabetes mellitus (DM) has been attracting much attention. In the present study, whether GF increase susceptibility to ischemia/reperfusion in the heart was investigated. METHODS AND RESULTS Male rats were randomly assigned to either a control, DM, and DM with GF group. DM was induced by an injection of streptozotocin, and glucose fluctuation was induced by starvation and insulin injection. One sequential program comprised 2 hypoglycemic episodes during 4 days. The isolated hearts were subjected to 20-min ischemia/30-min reperfusion. The infarct size was larger in hearts with GF than those with sustained hyperglycemia. Activities of catalase and superoxide dismutase were decreased, and expressions of NADPH oxidase and thioredoxin-interacting protein were upregulated by GF accompanied by an increase of reactive oxygen species (ROS). Swollen mitochondria with destroyed cristae were observed in diabetic hearts; they were further devastated by GF. Microarray analysis revealed that the expressions of microRNA (miRNA)-200c and miRNA-141 were abundant in those hearts with GF. Overexpression of miRNA-200c and miRNA-141 decreased mitochondrial superoxide dismutase and catalase activities, and increased ROS levels. Meanwhile, knockdown of miRNA-200c and miRNA-141 significantly decreased ROS levels in cardiomyocytes exposed to GF. CONCLUSIONS GF increased ROS generation and enhanced ischemia/reperfusion injury in the diabetic heart. Upregulated miRNA-200c and miRNA-141 may account for the increased ROS.

High-glucose condition reduces cardioprotective effects of insulin against mechanical stress-induced cell injury

AIMS Mechanical stress induces cardiomyocyte injury and contributes to the progression of heart failure in patients with hypertension. In this study, we investigated whether insulin exerts cardioprotective effects against mechanical stretching-induced cell injury, and whether the protective effect is influenced by high-glucose condition. MAIN METHODS Cultured neonatal rat cardiomyocytes were plated on silicone chambers, and the cells were mechanically stretched by 15% to induce cell injury. KEY FINDINGS Mechanical stretching increased reactive oxygen species (ROS) and decreased mitochondrial inner membrane potential (DeltaPsi(m)), eventually leading to cell death by apoptosis and necrosis. Insulin activated the phosphoinositide 3 (PI3) kinase/Akt pathway and reduced apoptosis and necrosis by suppressing ROS increase and preserving DeltaPsi(m). However, high-glucose condition attenuated the insulin-induced Akt phosphorylation and cardioprotection. To investigate the mechanisms that attenuated the effects of insulin in high-glucose condition, we examined the expression of tensin homologue deleted on chromosome 10 (PTEN), which is a negative regulator of the PI3 kinase/Akt pathway. The expressions of PTEN and phosphorylated PTEN were significantly decreased by insulin, and those effects were attenuated in high-glucose condition. SIGNIFICANCE The present results suggest that insulin prevents mechanical stress-induced cell injury which otherwise lead to heart failure. Furthermore, we found that high-glucose condition prevented the decrease in PTEN expression and the cardioprotective effects induced by insulin.