miR-124 is upregulated in diabetic mice and inhibits proliferation and promotes apoptosis of high-glucose-induced ß-cells by targeting EZH2.

BACKGROUND: Diabetes is a chronic metabolic disease, and a variety of miRNA are involved in the occurrence and development of diabetes. In clinical studies, miR-124 is highly expressed in the serum of patients with diabetes and in pancreatic islet ß-cells. However, few reports exist concerning the role and mechanism of action of miR-124 in diabetes. AIM: To investigate the expression of miR-124 in diabetic mice and the potential mechanism of action in islet ß-cells. METHODS: The expression levels of miR-124 and enhancer of zeste homolog 2 (EZH2) in pancreatic tissues of diabetic mice were detected. The targeted relationship between miR-124 and EZH2 was predicted by Targetscan software and verified by a double luciferase reporter assay. Mouse islet ß-cells Min6 were grown in a high glucose (HG) medium to mimic a diabetes model. The insulin secretion, proliferation, cell cycle and apoptosis of HG-induced Min6 cells were detected after interference of miR-124a and/or EZH2. RESULTS: The expression of miR-124 was upregulated and EZH2 was downregulated in the pancreatic tissue of diabetic mice compared with control mice, and the expression of miR-124 was negatively correlated with that of EZH2. miR-124 was highly expressed in HG-induced Min6 cells. Inhibition of miR-124 promoted insulin secretion and cell proliferation, induced the transition from the G0/G1 phase to the S phase of the cell cycle, and inhibited cell apoptosis in HG-induced Min6 cells. EZH2 was one of the targets of miR-124. Co-transfection of miR-124 inhibitor and siRNA-EZH2 could reverse the effects of the miR-124 inhibitor in HG-induced Min6 cells. CONCLUSION: miR-124 is highly expressed in diabetic mice and HG-induced Min6 cells and regulates insulin secretion, proliferation and apoptosis of islet ß-cells by targeting EZH2.

Resting Cardiac Power Predicts Adverse Outcome in Heart Failure Patients With Preserved Ejection Fraction: A Prospective Study.

Background: We sought to explore the significance of resting cardiac power/mass in predicting adverse outcome in patients with heart failure with preserved ejection fraction (HFpEF). Methods: This prospective cohort study included patients with HFpEF and without significant valve disease or right ventricular dysfunction. Cardiac power was normalized to left ventricular (LV) mass and expressed in W/100 g of LV myocardium. Multivariate Cox regression analysis was used to evaluate the association between resting cardiac power/mass and composite endpoint, which included all-cause mortality and heart failure (HF) hospitalization. Results: A total of 2,089 patients were included in this study. After an average follow-up of 4.4 years, 612 (29.30%) patients had composite endpoint, in which 331 (15.84%) died and 391 (18.72%) experienced HF hospitalization. In multivariate Cox regression analysis, resting power/mass < 0.7 W/m2 was independently associated with composite endpoint, all-cause mortality, cardiovascular mortality and HF hospitalization, with hazard ratios (HR) of 1.309 [95% confidence interval (CI): 1.108-1.546, P = 0.002], 1.697 (95%CI: 1.344-2.143, P < 0.001), 2.513 (95%CI: 1.711-3.689, P < 0.001), and 1.294 (95%CI: 1.052-1.592, P = 0.015), respectively. For composite endpoint, cardiovascular mortality and HF hospitalization, the C statistic increased significantly when incorporating resting cardiac power/mass into a model with established risk factors. For composite endpoint, the continuous net reclassification index after adding resting cardiac power/mass in the original model with N-terminal pro-brain natriuretic peptide was 13.1% (95%CI: 2.9-21.6%, P = 0.007), and the integrated discrimination index was 1.9% (95%CI: 0.8-3.2%, P < 0.001). Conclusion: Resting cardiac power determined by non-invasive echocardiography is independently associated with the risk of adverse outcomes in HFpEF patients and provides incremental prognostic information.

Notch inhibitor mitigates renal ischemia­reperfusion injury in diabetic rats.

Diabetes mellitus can exacerbate renal ischemia­reperfusion (I/R) injury (RI/RI) in diabetic rats. Previous studies have shown that Notch signaling is involved in renal disorders. The aim of the present study was to evaluate the protective effect of the Notch inhibitor γ­secretase N­[N­(3,5­difluorophenacetyl)­L­alanyl]­S­phenylglycine t­butyl ester (DAPT) on RI/RI in a streptozocin (STZ)­induced diabetic rat model. STZ­induced diabetic rats were randomly grouped for different treatments. Cisplatin was used to trigger the Notch signaling pathway and the animals were preconditioned with DAPT to block the signaling pathway. Renal function, oxidative stress and inflammatory factors were examined. DAPT­treated diabetic rats demonstrated mitigated renal injury and function, antioxidative activity was significantly improved and HIF­1a was upregulated. Notch inhibitor DAPT is a potential therapeutic target to improve the outcome of RI/RI in STZ­induced diabetic rats in part via the regulation of anti­oxidation and HIF­1a.