Objective This study investigated if resveratrol ameliorates diabetic cardiomyopathy by targeting associated oxidative stress mechanisms. Method Type 1 diabetes mellitus (DM) in FVB mice was induced by several intraperitoneal injections of a low dose of streptozotocin. Hyperglycemic and age-matched control mice were given resveratrol (10 mg/kg per day) for 1 month and subsequently monitored for an additional 6 months. Mice were assigned to four groups: control, resveratrol, DM, and DM/resveratrol. Cardiac function and blood pressure were assessed at 1, 3, and 6 months after DM induction. Oxidative damage and cardiac fibrosis were analyzed by histopathology, real-time PCR, and Western blot. Result Mice in the DM group exhibited increased blood glucose levels, cardiac dysfunction, and high blood pressure at 1, 3, and 6 months after DM induction. Resveratrol did not significantly affect blood glucose levels and blood pressure; however, resveratrol attenuated cardiac dysfunction and hypertrophy in DM mice. Resveratrol also reduced DM-induced fibrosis. In addition, DM mice hearts exhibited increased oxidative damage, as evidenced by elevated accumulation of 3-nitrotyrosine and 4-hydroxynonenal, which were both attenuated by resveratrol. Mechanistically, resveratrol increased NFE2-related factor 2 (Nrf2) expression and transcriptional activity, as well as Nrf2's downstream antioxidative targets. Conclusion We demonstrated that resveratrol prevents DM-induced cardiomyopathy, in part, by increasing Nrf2 expression and transcriptional activity.
Objectives. Elevated plasma homocysteine (Hcy) could lead to endothelial dysfunction and is viewed as an independent risk factor for atherosclerosis. Heat shock protein 27 (HSP27), a small heat shock protein, is reported to exert protective effect against atherosclerosis. This study aims to investigate the protective effect of HSP27 against Hcy-induced endothelial cell apoptosis in human umbilical vein endothelial cells (HUVECs) and to determine the underlying mechanisms. Methods. Apoptosis, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) of normal or HSP27-overexpressing HUVECs in the presence of Hcy were analyzed by flow cytometry. The mRNA and protein expression levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Results. We found that Hcy could induce cell apoptosis with corresponding decrease of nitric oxide (NO) level, increase of endothelin-1 (ET-1), intracellular adhesion molecule-1 (ICAM-1), vascular cellular adhesion molecule-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) levels, elevation of ROS, and dissipation of MMP. In addition, HSP27 could protect the cell against Hcy-induced apoptosis and inhibit the effect of Hcy on HUVECs. Furthermore, HSP27 could increase the ratio of Bcl-2/Bax and inhibit caspase-3 activity. Conclusions. Therefore, we concluded that HSP27 played a protective role against Hcy-induced endothelial apoptosis through modulation of ROS production and the mitochondrial caspase-dependent apoptotic pathway.
Background/Aims: The myocardial energy metabolism shift is one of the most important pathological features of ischemic heart disease (IHD). Although several microRNAs (miRs) are involved in the regulation of myocardial energy metabolism, their exact effects and underlying mechanisms remain unclear. The aim of this study was to investigate whether microRNA(miR-210) regulates the energy metabolism shift during oxidative stress in H9c2 cardiomyocytes. Methods: Cell survival was analyzed via CCK assay. The energy metabolism shift was detected by lactate assay, ATP assay and RT2 profiler glucose metabolism PCR array. Protein and mRNA expression levels were determined by western blot and qPCR. We also used kits to detect the activity of Complex I, Sirt3 and the NAD+/NADH ratio. Results: We determined that miR-210 promoted the energy metabolism shift. The iron-sulfur cluster assembly protein (ISCU) was a target of miR-210. Additionally, we detected the activity of complex I and found that miR-210 inhibits mitochondrial respiration. Interestingly, miR-210 may also indirectly regulate SIRT3 by regulating ISCU. Conclusion: Our results confirm that miR-210 is essential and sufficient for modulating the cellular energy metabolism shift during H2O2-induced oxidative stress in H9c2 cardiomyocytes by targeting ISCU.
Oxidative stress induces endothelial cell apoptosis and promotes atherosclerosis development. MicroRNA-210 (miR-210) is linked with apoptosis in different cell types. This study aimed to investigate the role of miR-210 in human umbilical vein endothelial cells (HUVECs) under oxidative stress and to determine the underlying mechanism. HUVECs were treated with different concentrations of hydrogen peroxide (H2O2), and cell viability was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and ATP assay. To evaluate the role of miR-210 in H2O2-mediated apoptosis, gain-and-loss-of-function approaches were used, and the effects on apoptosis and reactive oxygen species (ROS) level were assayed using flow cytometry. Moreover, miR-210 expression was detected by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and expression of the following apoptosis-related genes was assessed by qRT-PCR and Western blot at the RNA and protein level, respectively: caspase-8-associated protein 2 (CASP8AP2), caspase-8, and caspase-3. The results showed that H2O2 induced apoptosis in HUVECs in a dose-dependent manner and increased miR-210 expression. Overexpression of miR-210 inhibited apoptosis and reduced ROS level in HUVECs treated with H2O2. Furthermore, miR-210 downregulated CASP8AP2 and related downstream caspases at protein level. Thus, under oxidative stress, miR-210 has a prosurvival and antiapoptotic effect on HUVECs by reducing ROS generation and downregulating the CASP8AP2 pathway.
In this study, we aimed to explore the mechanism of glutathione peroxidase 3 (GPX3) in the growth of malignant melanoma (MM) cells by hypoxia‐inducible factor‐1α (HIF1‐α) and HIF2‐α regulating the metabolism through reactive oxygen species (ROS). The messenger RNA and protein expression of GPX3, HIF1‐α, HIF2‐α in tissues, and cell lines were measured by reverse transcription‐quantitative PCR and Western blot analysis. A375 cells were transfected with GPX3 overexpression plasmid, small interfering RNA (siRNA) targeting GPX3, or siRNA targeting HIF1‐α/HIF2‐α to upregulate or downregulate the expression of GPX3 or HIF1‐α/HIF2‐α. The effects of H2O2 and N‐acetylcysteine (NAC) on the levels of HIF1‐α and HIF2‐α after overexpression of GPX3 were studied. The cell viability was detected by Cell Counting Kit‐8. The levels of ROS, glucose uptake and lactic acid production, oxidative phosphorylation, and glycolysis of cells were measured for assessment of cellular metabolism. The expression of GPX3 decreased, while ROS, HIF1‐α, and HIF2‐α increased in MM tissues and cells. Overexpression of GPX3 inhibited the viability of MM cells and the growth of melanoma xenografts. The overexpression of GPX3 reduced the glucose uptake, extracellular lactic acid content, and extracellular acidification rate and increased the oxygen consumption rate level. Overexpression of GPX3 could reduce the levels of HIF1‐α and HIF2‐α, which could regulate metabolic levels. GPX3 reduced ROS level in MM to inhibit HIF1‐α and HIF2‐α. The addition of H2O2 increased while NAC reduced the protein levels of HIF1‐α and HIF2‐α in the cells overexpressing GPX3. Our study demonstrates that GPX3 inhibits the growth of MM cells through its inhibitory effect on cell metabolic disorder by inhibiting HIF1‐α via regulating ROS.
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