Protection by dimethyl fumarate against diabetic cardiomyopathy in type 1 diabetic mice likely via activation of nuclear factor erythroid-2 related factor 2

The present study tested whether MG132 increases vascular nuclear factor E2-related factor-2 (Nrf2) expression and transcription to provide a therapeutic effect on diabetes-induced pathogenic changes in the aorta. To this end, three-month-old OVE26 diabetic and age-matched control mice were intraperitoneally injected with MG-132, 10 μg/kg daily for 3 months. OVE26 transgenic type 1 diabetic mice develop hyperglycemia at 2-3 weeks of age and exhibit albuminuria at 3 months of age with mild increases in TNF-αexpression and 3-NT accumulation in the aorta. Diabetes-induced significant increases in the wall thickness and structural derangement of aorta were found in OVE26 mice with significant increases in aortic oxidative and nitrosative damage, inflammation, and remodeling at 6 months of diabetes, but not at 3 months of diabetes. However, these pathological changes seen at the 6 months of diabetes were abolished in OVE26 mice treated with MG-132 for 3 months that were also associated with a significant increase in Nrf2 expression in the aorta as well as transcription of downstream genes. These results suggest that chronic treatment with low-dose MG132 can afford an effective therapy for diabetes-induced pathogenic changes in the aorta, which is associated with the increased Nrf2 expression and transcription.

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Nuclear Factor Erythroid 2-Related Factor 2 Deletion Impairs Glucose Tolerance and Exacerbates Hyperglycemia in Type 1 Diabetic Mice

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.109.162271 ◽

2010 ◽

Vol 333 (1) ◽

pp. 140-151 ◽

Cited By ~ 67

Author(s):

Lauren M. Aleksunes ◽

Scott A. Reisman ◽

Ronnie L. Yeager ◽

Michael J. Goedken ◽

Curtis D. Klaassen

Keyword(s):

Glucose Tolerance ◽

Related Factor ◽

Nuclear Factor ◽

Diabetic Mice

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Abstract 26: Fibroblast Growth Factor 21 Prevents Diabetic Cardiomyopathy by Attenuating Cardiac Lipotoxicity via Erk1/2-dependent Signaling Pathway in Mice

Circulation Research ◽

10.1161/res.117.suppl_1.26 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Yi Tan ◽

Chi Zhang ◽

Xiaoqing Yan ◽

Zhifeng Huang ◽

Junlian Gu ◽

...

Keyword(s):

Cell Death ◽

Type 1 Diabetes ◽

Signaling Pathway ◽

P38 Mapk ◽

Diabetic Cardiomyopathy ◽

Cardiac Cell ◽

Diabetic Mice ◽

Ampk Signaling

The role of FGF21 plays in the development and progression of diabetic cardiomyopathy (DCM) has not been addressed. Here we demonstrated that type 1 diabetes decreased FGF21 levels in the blood, but up-regulated cardiac fgf21 expression about 40 fold at 2 months and 3-1.5 fold at 4 and 6 months after diabetes, which indicated a cardiac specific FGF21 adaptive up-regulation. To define the critical role of FGF21 in DCM, type 1 diabetes was induced in FGF21 knock out (FGF21KO) mice. At 1, 2 and 4 months after diabetes onset, no significant differences between FGF21KO and wild type (WT) diabetic mice in blood glucose and triglyceride levels were observed. But FGF21KO diabetic mice showed earlier and more severe cardiac dysfunction, remodeling and oxidative stress, as well as greater increase in cardiac lipid accumulation than WT diabetic mice. Mechanistically, FGF21 reduced palmitate-induced cardiac cell death, which was accompanied by up-regulation of cardiac Erk1/2, p38 MAPK and AMPK phosphorylation. Inhibition of each kinase with its inhibitor and/ or siRNA revealed that FGF21 prevents palmitate-induced cardiac cell death via up-regulating the Erk1/2-dependent p38 MAPK/AMPK signaling pathway. In vivo administration of FGF21, but not FGF21 plus ERK1/2 inhibitor, to diabetic mice significantly prevented cardiac cell death and reduced inactivation of Erk1/2, p38 MAPK and AMPK, and prevented cardiac remodeling and dysfunction at late-stage. Our results demonstrate that cardiac FGF21 decompensation may contribute to the development of DCM and FGF21 may be a therapeutic target for the treatment of diabetic cardiac damage via activation of Erk1/2-P38 MAPK-AMPK signaling.

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Autophagy inhibition enables Nrf2 to exaggerate the progression of diabetic cardiomyopathy in mice

10.2337/figshare.12937733 ◽

2020 ◽

Author(s):

Ada Admin ◽

Huimei Zang ◽

Weiwei Wu ◽

Lei Qi ◽

Wenbin Tan ◽

...

Keyword(s):

Diabetic Cardiomyopathy ◽

Cardiac Dysfunction ◽

Antioxidant Defense ◽

Myocardial Damage ◽

Related Factor ◽

Nrf2 Knockout ◽

Underlying Mechanisms ◽

Autophagy Inhibition ◽

And Oxidative Stress

Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) may either ameliorate or worsen diabetic cardiomyopathy. However, the underlying mechanisms are poorly understood. Herein we report a novel mechanism of Nrf2-mediated myocardial damage in type 1 diabetes (T1D). Global Nrf2 knockout (Nrf2KO) hardly affected the onset of cardiac dysfunction induced by T1D but slowed down its progression in mice independent of sex. In addition, Nrf2KO inhibited cardiac pathological remodeling, apoptosis and oxidative stress associated with both onset and advancement of cardiac dysfunction in T1D. Such Nrf2-mediated progression of diabetic cardiomyopathy was confirmed by cardiomyocyte-restricted (CR) Nrf2 transgenic (Tg) approach in mice. Moreover, cardiac autophagy inhibition via CR KO of autophagy related 5 gene (CR-Atg5KO) led to early onset and accelerated development of cardiomyopathy in T1D, and CR-Atg5KO-induced adverse phenotypes were rescued by additional Nrf2KO. Mechanistically, chronic T1D leads to glucolipotoxicity inhibiting autolysosome efflux, which in turn intensifies Nrf2-driven transcription to fuel lipid peroxidation while inactivating Nrf2-mediated antioxidant defense and impairing Nrf2-coordinated iron metabolism, thereby leading to ferroptosis in cardiomyocytes. These results demonstrate that diabetes over time causes autophagy deficiency, which turns off Nrf2-mediated defense while switching on Nrf2-operated pathological program toward ferroptosis in cardiomyocytes, thereby worsening the progression of diabetic cardiomyopathy.

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Autophagy inhibition enables Nrf2 to exaggerate the progression of diabetic cardiomyopathy in mice

10.2337/figshare.12937733.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Huimei Zang ◽

Weiwei Wu ◽

Lei Qi ◽

Wenbin Tan ◽

...

Keyword(s):

Diabetic Cardiomyopathy ◽

Cardiac Dysfunction ◽

Antioxidant Defense ◽

Myocardial Damage ◽

Related Factor ◽

Nrf2 Knockout ◽

Underlying Mechanisms ◽

Autophagy Inhibition ◽

And Oxidative Stress

Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) may either ameliorate or worsen diabetic cardiomyopathy. However, the underlying mechanisms are poorly understood. Herein we report a novel mechanism of Nrf2-mediated myocardial damage in type 1 diabetes (T1D). Global Nrf2 knockout (Nrf2KO) hardly affected the onset of cardiac dysfunction induced by T1D but slowed down its progression in mice independent of sex. In addition, Nrf2KO inhibited cardiac pathological remodeling, apoptosis and oxidative stress associated with both onset and advancement of cardiac dysfunction in T1D. Such Nrf2-mediated progression of diabetic cardiomyopathy was confirmed by cardiomyocyte-restricted (CR) Nrf2 transgenic (Tg) approach in mice. Moreover, cardiac autophagy inhibition via CR KO of autophagy related 5 gene (CR-Atg5KO) led to early onset and accelerated development of cardiomyopathy in T1D, and CR-Atg5KO-induced adverse phenotypes were rescued by additional Nrf2KO. Mechanistically, chronic T1D leads to glucolipotoxicity inhibiting autolysosome efflux, which in turn intensifies Nrf2-driven transcription to fuel lipid peroxidation while inactivating Nrf2-mediated antioxidant defense and impairing Nrf2-coordinated iron metabolism, thereby leading to ferroptosis in cardiomyocytes. These results demonstrate that diabetes over time causes autophagy deficiency, which turns off Nrf2-mediated defense while switching on Nrf2-operated pathological program toward ferroptosis in cardiomyocytes, thereby worsening the progression of diabetic cardiomyopathy.

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HDAC3 inhibition in diabetic mice may activate Nrf2 preventing diabetes-induced liver damage and FGF21 synthesis and secretion leading to aortic protection

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00465.2017 ◽

2018 ◽

Vol 315 (2) ◽

pp. E150-E162 ◽

Cited By ~ 11

Author(s):

Jian Zhang ◽

Zheng Xu ◽

Junlian Gu ◽

Saizhi Jiang ◽

Quan Liu ◽

...

Keyword(s):

Nuclear Translocation ◽

Hdac Inhibitors ◽

Vascular Complications ◽

Specific Inhibitor ◽

Histone Deacetylation ◽

Fibroblast Growth Factor 21 ◽

Related Factor ◽

Diabetic Mice ◽

Protein Levels

Vascular complications are common pathologies associated with type 1 diabetes. In recent years, histone deacetylation enzyme (HDAC) inhibitors have been shown to be successful in preventing atherosclerosis. To investigate the mechanism for HDAC3 inhibition in preventing diabetic aortic pathologies, male OVE26 type 1 diabetic mice and age-matched wild-type (FVB) mice were given the HDAC3-specific inhibitor RGFP-966 or vehicle for 3 mo. These mice were then euthanized immediately or maintained for an additional 3 mo without treatment. Levels of aortic inflammation and fibrosis and plasma and fibroblast growth factor 21 (FGF21) levels were determined. Because the liver is the major organ for FGF21 synthesis in diabetic animals, the effects of HDAC3 inhibition on hepatic FGF21 synthesis were examined. Additionally, hepatic miR-200a and kelch-like ECH-associated protein 1 (Keap1) expression and nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation were measured. HDAC3 inhibition significantly reduced aortic fibrosis and inflammation in OVE26 mice at both 3 and 6 mo. Plasma FGF21 levels were significantly higher in RGFP-966-treated OVE26 mice compared with vehicle-treated mice at both time points. It also significantly reduced hepatic pathologies associated with diabetes, accompanied by increased FGF21 mRNA and protein expression. HDAC3 inhibition also increased miR-200a expression, reduced Keap1 protein levels, and increased Nrf2 nuclear translocation with an upregulation of antioxidant gene and FGF21 transcription. Our results support a model where HDAC3 inhibition may promote Nrf2 activity by increasing miR-200a expression with a concomitant decrease in Keap1 to preserve hepatic FGF21 synthesis. The preservation of hepatic FGF21 synthesis ultimately leads to a reduction in diabetes-induced aorta pathologies.

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Abstract 315: Coenzyme Q 10 Protects Against Diabetes-Induced Diastolic Dysfunction and Adverse Cardiac Remodeling in a Mouse Model of Type 1 Diabetes

Circulation Research ◽

10.1161/res.111.suppl_1.a315 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Karina Huynh ◽

Helen Kiriazis ◽

Xiao-Jun Du ◽

Jane E Love ◽

Karin Jandeleit-Dahm ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diastolic Dysfunction ◽

Olive Oil ◽

Diabetic Cardiomyopathy ◽

Cardiac Remodeling ◽

Coenzyme Q ◽

Left Ventricular ◽

Diabetic Patients ◽

Diabetic Mice

Diastolic dysfunction is often the earliest manifestation of diabetic cardiomyopathy, usually accompanied by adverse cardiac remodeling and increased oxidative stress. We tested the hypothesis that administration of Coenzyme Q 10 (CoQ) attenuates type 1 diabetes-induced left ventricular (LV) dysfunction and remodeling. Further, we aimed to compare the efficacy of CoQ to the ACEI, ramipril. Male 6-week old mice received either streptozotocin (STZ, 55mg/kg/day for 5 days) to induce diabetes, or citrate buffer. After 4 weeks, mice were treated with either CoQ dissolved in olive oil (10mg/kg/day), olive oil alone, ramipril (3mg/kg/day) or left untreated for 8 weeks (n=11-14/group). Diabetic mice had increased blood glucose levels compared with non-diabetic controls. Superoxide (O 2 - ) production was enhanced in untreated diabetic mice, and attenuated with CoQ treatment. Diastolic function was impaired in diabetic mice, on Doppler echocardiography (E/A ratio, deceleration time DT) and catheterization (LV end diastolic pressure EDP and LV-dP/dt). Administration of CoQ ameliorated diastolic dysfunction on E/A ratio, DT and LVEDP in diabetic mice, with a similar trend on LV-dP/dt. Although DT and LVEDP were improved with ramipril treatment, E/A ratio was not. Diabetic mice also exhibited cardiomyocyte hypertrophy (H&E staining), cardiac fibrosis (Sirius red staining) and increased apoptosis. Both CoQ and ramipril reduced these markers of adverse LV remodeling. In conclusion, these data suggest that both CoQ and ramipril can attenuate diabetic cardiomyopathy. Addition of CoQ to standard care may offer improved treatment of diastolic dysfunction in diabetic patients.

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Abstract 305: Carvacrol Attenuates Diabetic Cardiomyopathy by Enhancing PI3K/AKT Pathway in STZ-induced Type 1 Diabetic C57BL/6J Mice

Circulation Research ◽

10.1161/res.119.suppl_1.305 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Ning Hou ◽

Yunpei Mai ◽

Wenliang Chen ◽

Faqian Li ◽

Jiandong Luo

Keyword(s):

Western Blotting ◽

Diabetic Cardiomyopathy ◽

Plasma Concentrations ◽

Akt Pathway ◽

Dependent Manner ◽

Diabetic Mice ◽

Diabetes Group ◽

Protein Levels ◽

Group I

Background: Carvacrol (CAR), a monoterpenic phenol that occurs in many essential oils of the family Labiatae including Origanum , Satureja , Thymbra , Thymus , and Corydothymus species, possess a wide variety of pharmacological properties including antioxidant and anti-inflammatory potential. This present study was designed to investigate the cardiac protective effect of CAR on diabetic cardiomyopathy in STZ-induced type 1 diabetic mice and explore its potential molecular mechanism. Methods: Type 1 diabetes was induced by the intraperitoneal injection of streptozocin (STZ) to male mice at dose of 45 mg/kg body weight (BW). The diabetic animals were divided into three groups containing eight in each: Group I diabetes, Group II and II injected with CAR at 10 and 20 mg/kg BW respectively once daily for 6 weeks. Age matched male C57 mice were used as normal controls. The plasma concentrations of glucose, total cholesterol (TC) and triglycerides (TG) levels were enzymatically determined using commercial kits. The cardiac function was measured by echocardiography. Protein levels of p-PDK1/t-PDK1, p-AKT/t-AKT, p-GSKα/β/t-GSKα/β were detected by Western blotting. Results: STZ-induced C57BL/6J diabetic mice showed an elevation in serum glucose, TG and TC level. Compared to diabetic mice, administration of CAR resulted in significant decrease ( P <0.05) in plasma glucose level in a dose dependent manner, but did not attenuate elevation in TG and TC levels. The abnormal diastolic function in type 1 diabetic mice was significantly reversed by CAR administration. Furthermore, western blotting showed that the expression of p-PDK1, p-AKT and p-GSKα/β were lower in diabetic hearts than C57 hearts while total PDK1, AKT and GSK α/β protein levels were no difference among groups. CAR administration attenuated these decreases in protein phosphorylation. These findings indicate that the impaired PI3K/AKT pathway induced by STZ in diabetic heart can be restored by CAR. Conclusion: Carvacrol has antidiabetic property and can be potentially used to prevent hyperglycemia and diabetic cardiomyopathy.

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Neuroprotective effect of dimethyl fumarate in stroke: The role of nuclear factor erythroid 2-related factor 2

Iranian Journal of Neurology ◽

10.18502/ijnl.v18i3.1633 ◽

2019 ◽

Author(s):

Anahid Safari ◽

Hamzeh Badeli-Sarkala2 ◽

Mohammad Reza Namavar ◽

Elias Kargar-Abarghouei ◽

Neda Anssari ◽

...

Keyword(s):

Middle Cerebral Artery ◽

Infarct Volume ◽

Dimethyl Fumarate ◽

Treated Group ◽

Vehicle Group ◽

Related Factor ◽

Nuclear Factor ◽

Neuroprotective Effects ◽

Total Brain ◽

Nrf2 Expression

Background: There is evidence that supports the neuroprotective effects of dimethyl fumarate (DMF) in stroke. Nuclear factor erythroid 2-related factor 2 (Nrf2) has both anti-oxidant and anti-inflammatory mechanisms. We investigated the neuroprotective effects of DMF via Nrf2 activation in the cortex, striatum, and diencephalon in a middle cerebral artery occlusion (MCAO) model of stroke. Methods: 22 Sprague-Dawley male rats were randomized into 3 groups. In DMF-treated group (n = 8), rats received 15 mg/kg oral DMF twice daily by gavage from day 0 to 14 after a 60-minute MCAO. The vehicle group (n = 7) underwent MCAO and were given methocel/H2O, using the same method and schedule. In the sham group (n = 7), neck was opened, but neither middle cerebral artery (MCA) was occluded nor any drug was administered. After 14 days, the animals were sacrificed. The infarct volume were assessed by stereology method. Nrf2 expression was evaluated in the cortex, striatum, and diencephalon by immunohistochemistry method. Results: Ratio of infarct to total brain volume was significantly lower in the DMF-treated group (5.76%) in comparison with the vehicle group (22.39%) (P < 0.0001). Nrf2 expression was higher in DMFtreated group in comparison with both the vehicle and sham groups in cortex, striatum, diencephalon, and total brain (P < 0.0001). In the DMF-treated group, significant negative correlation between Nrf2 expression and infarct volume was observed in cortex, striatum, diencephalon, and total brain. Conclusion: DMF induces Nrf2 expression and its neuroprotective effects in different brain anatomical regions.

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