Activation of NF-E2-Related Factor-2 Reverses Biochemical Dysfunction of Endothelial Cells Induced by Hyperglycemia Linked to Vascular Disease (original) (raw)
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Oxidative medicine and cellular longevity, 2014
Type 2 diabetes mellitus (T2DM) significantly increases risk for vascular complications. Diabetes-induced aorta pathological changes are predominantly attributed to oxidative stress. Nuclear factor E2-related factor-2 (Nrf2) is a transcription factor orchestrating antioxidant and cytoprotective responses to oxidative stress. Sulforaphane protects against oxidative damage by increasing Nrf2 expression and its downstream target genes. Here we explored the protective effect of sulforaphane on T2DM-induced aortic pathogenic changes in C57BL/6J mice which were fed with high-fat diet for 3 months, followed by a treatment with streptozotocin at 100 mg/kg body weight. Diabetic and nondiabetic mice were randomly divided into groups with and without 4-month sulforaphane treatment. Aorta of T2DM mice exhibited significant increases in the wall thickness and structural derangement, along with significant increases in fibrosis (connective tissue growth factor and transforming growth factor), inf...
Nutrition & Metabolism, 2012
Background Oxidative stress plays an important role in diabetes-induced vascular inflammation and pathogenesis. Nuclear factor E2-related factor-2 (Nrf2) is a transcription factor orchestrating antioxidant and cyto-protective responses to oxidative stress. In the present study, we tested whether sulforaphane (SFN) can protect the aorta from diabetes and, if so, whether the aortic protection is associated with up-regulation of Nrf2 and its down-stream antioxidants. Methods Type 1 diabetes was induced in FVB mice by multiple low-dose streptozotocin. Diabetic and age-matched control mice were treated with or without SFN at 0.5 mg/kg daily in five days of each week for three months. At the end of 3 months treatment of SFN one set of mice were sacrificed to perform the experimental measurements. The second set of both diabetic and control mice were aged for additional 3 months without further SFN treatment and then sacrificed to perform the experimental measurements. Aortas from these mi...
Scientific reports, 2017
In this study we investigate pyridoxamine (PM) and/or sulforaphane (SFN) as therapeutic interventions to determine whether activators of NFE2-related factor 2 (Nrf2) can be used in addition with inhibitors of advanced glycation end products (AGE) formation to attenuate oxidative stress and improve endothelial dysfunction in type 2 diabetes. Goto-kakizaki (GK) rats, an animal model of non-obese type 2 diabetes, were treated with or without PM and/or SFN during 8 weeks and compared with age-matched Wistar rats. At the end of the treatment, nitric oxide (NO)-dependent and independent vasorelaxation in isolated aorta and mesenteric arteries were evaluated. Metabolic profile, NO bioavailability and vascular oxidative stress, AGE and Nrf2 levels were also assessed. Diabetic GK rats presented significantly lower levels of Nrf2 and concomitantly exhibited higher levels of oxidative stress and endothelial dysfunction. PM and SFN as monotherapy were capable of significantly improving endothel...
Archives of Medical Science
Introduction: Sulodexide (SDX) is used for the treatment of many vascular disorders due to its anticoagulant, anti-inflammatory and anti-atherosclerotic properties. However, the detailed molecular mechanism of its endothelioprotective action is still not completely understood. There is increasing evidence suggesting that antioxidant enzymes play an important role in anti-ischemic properties of SDX. We postulate that up-regulation of glutathione-S-transferase P1 (GSTP1) mediated by the transcription factor Nrf2 could be associated with the antioxidant effect of SDX on vascular endothelial cells. Material and methods: In the present study, we investigated whether SDX affects GSTP1 and Nrf2 in oxygen glucose deprivation (OGD) treated human umbilical vein endothelial cells (HUVECs). The cells treated with/without SDX (0.5 LRU/ml) were subjected to OGD for 1-6 h. To study the influence of SDX on the Nrf2 nucleus accumulation, the cells were incubated with 0.5 LRU/ml SDX in OGD for 1 h. Results: We found that after short-term OGD (1-3 h), the drug increased the expression of both GSTP1 and Nrf2 mRNA/protein in HUVECs (p < 0.05), as determined by real-time PCR and enzyme-linked immunosorbent assay (ELISA). SDX treatment also enhanced the nuclear accumulation of Nrf2 in HUVECs after 1 h of OGD (p < 0.05). Conclusions: SDX induces a rapid onset of the antioxidant response by up-regulating the expression of GSTP1 and Nrf2 in endothelial cells subjected to in vitro simulated ischemia.
Frontiers in Pharmacology
Background: Diabetes mellitus leads to endothelial dysfunction and accumulation of oxygen radicals. Sulfasalazine-induced Nrf2 activation reduces oxidative stress in vessels. Thus, in the present study, we investigated the effects of sulfasalazine on endothelial dysfunction induced by high glucose. We also ascribed the underlying mechanism involved in glucose-induced endothelial dysfunction.Methods: For this experiment we used 80 Wistar Albino rats thoracic aorta to calculate the dose response curve of noradrenaline and acetylcholine. Vessels were incubated in normal and high glucose for 2 h. To investigate glucose and sulfasalazine effects the vessels of the high glucose group were pre-treated with sulfasalazine (300 mM), JNK inhibitor (SP600125), and ERK inhibitor (U0126) for 30 min. The dose response curve was calculated through organ bath. The eNOS, TAS, TOS, and HO-1 levels were estimated by commercially available ELISA kits.Results: In the high glucose group, the Emax for cont...
Sulforaphane inhibits endothelial lipase expression through NF-κB in endothelial cells
Atherosclerosis, 2010
Objective: Endothelial lipase (EL) is a new member of triacylglycerol lipase family that has been shown to decrease high-density lipoprotein (HDL) cholesterol levels leading to increased risk of atherosclerosis. Its expression is increased during inflammation and by inflammatory cytokines. Sulforaphane (SFN) is a naturally occurring isothiocyanate present in cruciferous vegetables that has antioxidant and antiinflammatory effects. Nuclear factor (NF)-B is one of the molecular targets for SFN-mediated protective effects. Our aim was therefore to assess whether SFN could impact on EL expression via modulation of NF-B pathway.
American Journal of Physiology-Heart and Circulatory Physiology, 2011
Hyperglycemia in diabetes mellitus promotes oxidative stress in endothelial cells, which contributes to development of cardiovascular diseases. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a transcription factor activated by oxidative stress that regulates expression of numerous reactive oxygen species (ROS) detoxifying and antioxidant genes. This study was designed to elucidate the homeostatic role of adaptive induction of Nrf2-driven free radical detoxification mechanisms in endothelial protection under diabetic conditions. Using a Nrf2/antioxidant response element (ARE)-driven luciferase reporter gene assay we found that in a cultured coronary arterial endothelial cell model hyperglycemia (10–30 mmol/l glucose) significantly increases transcriptional activity of Nrf2 and upregulates the expression of the Nrf2 target genes NQO1, GCLC, and HMOX1. These effects of high glucose were significantly attenuated by small interfering RNA (siRNA) downregulation of Nrf2 or overexpre...
The Effect of Nrf2 on Diabetic Complications
A Master Regulator of Oxidative Stress - The Transcription Factor Nrf2, 2016
The Nrf2 has been identified as a key molecular player in orchestrating adaptive cellular interactions following a wide spectrum of cellular conditions that could be either extracellular or intracellular. The encoded transcription factor regulates genes, which contain antioxidant response elements (ARE) in their promoters; many of these genes encode proteins involved in response to environmental stress, detoxifying enzymes, metabolic enzymes, injury, and inflammation, which includes the production of free radicals. The association between oxidative stress and inflammation with progression of diabetic nephropathy and cardiomyopathy has been described. The prevention of diabetic nephropathy and cardiomyopathy has become a global concern for those who are working in diabetic care management. Therefore, activation of Nrf2 has the potential to protect against macromolecular damage. Studies have demonstrated the beneficial role of Nrf2 induction in the prevention of DN. Upon exposure of cells to oxidative stress or electrophilic compounds, Nrf2 dissociates from Keap1 and translocates into the nucleus to bind to antioxidant-responsive elements in the genes encoding antioxidant enzymes. Upregulation of these Nrf2-dependent antioxidants promotes detoxification and antiinflammatory function. Thus, the Nrf2 activators have been suggested for preventing diabetic nephropathy.