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

2018 ◽  
Vol 315 (2) ◽  
pp. E150-E162 ◽  
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.

scholarly journals O-GlcNAcase overexpression reverses coronary endothelial cell dysfunction in type 1 diabetic mice

2015 ◽  
Vol 309 (9) ◽  
pp. C593-C599 ◽  
Author(s):  
Ayako Makino ◽  
Anzhi Dai ◽  
Ying Han ◽  
Katia D. Youssef ◽  
Weihua Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Protein Modification ◽  
Control Level ◽  
Vascular Complications ◽  
Capillary Density ◽  
Diabetic Mice ◽  
Endothelium Dependent Relaxation

Cardiovascular disease is the primary cause of morbidity and mortality in diabetes, and endothelial dysfunction is commonly seen in these patients. Increased O-linked N-acetylglucosamine ( O-GlcNAc) protein modification is one of the central pathogenic features of diabetes. Modification of proteins by O-GlcNAc ( O-GlcNAcylation) is regulated by two key enzymes: β- N-acetylglucosaminidase [ O-GlcNAcase (OGA)], which catalyzes the reduction of protein O-GlcNAcylation, and O-GlcNAc transferase (OGT), which induces O-GlcNAcylation. However, it is not known whether reducing O-GlcNAcylation can improve endothelial dysfunction in diabetes. To examine the effect of endothelium-specific OGA overexpression on protein O-GlcNAcylation and coronary endothelial function in diabetic mice, we generated tetracycline-inducible, endothelium-specific OGA transgenic mice, and induced OGA by doxycycline administration in streptozotocin-induced type 1 diabetic mice. OGA protein expression was significantly decreased in mouse coronary endothelial cells (MCECs) isolated from diabetic mice compared with control MCECs, whereas OGT protein level was markedly increased. The level of protein O-GlcNAcylation was increased in diabetic compared with control mice, and OGA overexpression significantly decreased the level of protein O-GlcNAcylation in MCECs from diabetic mice. Capillary density in the left ventricle and endothelium-dependent relaxation in coronary arteries were significantly decreased in diabetes, while OGA overexpression increased capillary density to the control level and restored endothelium-dependent relaxation without changing endothelium-independent relaxation. We found that connexin 40 could be the potential target of O-GlcNAcylation that regulates the endothelial functions in diabetes. These data suggest that OGA overexpression in endothelial cells improves endothelial function and may have a beneficial effect on coronary vascular complications in diabetes.

scholarly journals Decreased Oocyte-Granulosa Cell Gap Junction Communication and Connexin Expression in a Type 1 Diabetic Mouse Model

2008 ◽  
Vol 22 (12) ◽  
pp. 2643-2654 ◽  
Author(s):  
Ann M. Ratchford ◽  
Cybill R. Esguerra ◽  
Kelle H. Moley
Keyword(s):  
Type 1 Diabetes ◽  
Mouse Model ◽  
Gap Junction ◽  
Granulosa Cell ◽  
Meiotic Maturation ◽  
Diabetic Mice ◽  
Protein Levels ◽  
Gap Junction Communication ◽  
Oocyte Meiotic Maturation

Abstract In women, type 1 diabetes is associated with an increased risk of poor prenatal outcomes such as congenital anomalies and early miscarriage. In murine models of type 1 diabetes, impaired oocyte meiotic maturation, abnormal oocyte metabolism, and increased granulosa cell apoptosis have been noted. because gap junction communication is critical for the regulation of oocyte growth and meiotic maturation, we investigated the level of communication between the oocyte and surrounding cumulus cells in a streptozotocin-induced type 1 diabetic B6SJL/F1 mouse model and the expression of gap junction proteins known as connexins. Fluorescence recovery after photobleaching analyses of cumulus cell-enclosed oocytes (CEOs) from diabetic mice showed a 60% decrease in communication as compared with CEOs from nondiabetic mice. Real-time RT-PCR analyses confirmed the presence of Cx26, Cx37, and Cx57 mRNA and revealed a significant decrease in Cx37 mRNA expression in oocytes from diabetic mice compared with nondiabetic mice. Western analyses detected Cx26 expression in CEO but not denuded oocyte (DO) samples, and Cx37 in DO samples. Cx26 protein levels were decreased by 78% in CEOs from diabetic mice, and Cx37 protein levels were decreased 36% in DOs from diabetic mice. This decrease in connexin expression and gap junction communication in CEOs from diabetic mice may be responsible for the impaired oocyte meiotic maturation and poor pregnancy outcomes.

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

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.

scholarly journals SP600125 suppresses Keap1 expression and results in NRF2-mediated prevention of diabetic nephropathy

2018 ◽  
Vol 60 (2) ◽  
pp. 145-157 ◽  
Author(s):  
Huan Zhang ◽  
Xiuxia Liu ◽  
Shanshan Zhou ◽  
Ye Jia ◽  
Ying Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Nuclear Translocation ◽  
Mesangial Cells ◽  
Critical Role ◽  
Antioxidant Defense System ◽  
Related Factor ◽  
Diabetic Mice ◽  
Nrf2 Protein

c-Jun N-terminal kinase (JNK) contributes to the pathogenesis of diabetic nephropathy (DN). The JNK inhibitor SP600125 was reported to ameliorate DN. However, the mechanism remained unclear. We previously reported that SP600125 activated nuclear factor erythroid 2-related factor 2 (NRF2), a governor of the cellular antioxidant defense system, in the aortas of the diabetic mice. Given the critical role of NRF2 in preventing DN, the present study aimed to test whether or not NRF2 is required for SP600125’s protection against DN. To test the role of NRF2 in SP600125’s effect, streptozotocin-induced C57BL/6 wild-type (WT) and Nrf2-knockout (KO) diabetic mice were treated in the presence or absence of SP600125, for 24 weeks. To explore the mechanism by which SP600125 activates NRF2, mouse mesangial cells (MMCs) were treated with high glucose (HG), in the presence or absence of either SP600125 or JNK siRNA. SP600125 significantly attenuated the diabetes-induced renal oxidative stress, inflammation, fibrosis, pathological change and dysfunction in the WT, but not the Nrf2 KO mice. SP600125 inactivated JNK, inhibited kelch-like ECH-associated protein 1 expression, preserved NRF2 protein and facilitated its nuclear translocation in the kidneys of the WT mice, the effects of which were similarly produced by either SP600125 or JNK siRNA in HG-treated MMCs. Further, both SP600125 and JNK siRNA alleviated HG-induced mesangial oxidative stress and expression of inflammatory and fibrotic genes. The present study demonstrates that NRF2 is required for SP600125’s protection against DN. SP600125 activates NRF2 possibly via inhibition of JNK-induced Keap1 expression.

scholarly journals Fibroblast growth factor 21 Ameliorates diabetes-induced endothelial dysfunction in mouse aorta via activation of the CaMKK2/AMPKα signaling pathway

2019 ◽  
Vol 10 (9) ◽  
Author(s):  
Lei Ying ◽  
Na Li ◽  
Zhengyue He ◽  
Xueqin Zeng ◽  
Yan Nan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Signaling Pathway ◽  
Oxidative Capacity ◽  
Fibroblast Growth Factor 21 ◽  
Diabetic Mice

Abstract Endothelial dysfunction initiates and exacerbates hypertension, atherosclerosis and other cardiovascular complications in diabetic mellitus. FGF21 is a hormone that mediates a number of beneficial effects relevant to metabolic disorders and their associated complications. Nevertheless, it remains unclear as to whether FGF21 ameliorates endothelial dysfunction. Therefore, we investigated the effect of FGF21 on endothelial function in both type 1 and type 2 diabetes. We found that FGF21 reduced hyperglycemia and ameliorated insulin resistance in type 2 diabetic mice, an effect that was totally lost in type 1 diabetic mice. However, FGF21 activated AMPKα, suppressing oxidative stress and enhancing endothelium-dependent vasorelaxation of aorta in both types, suggesting a mechanism that is independent of its glucose-lowering and insulin-sensitizing effects. In vitro, we identified a direct action of FGF21 on endothelial cells of the aorta, in which it bounds to FGF receptors to alleviate impaired endothelial function challenged with high glucose. Furthermore, the CaMKK2-AMPKα signaling pathway was activated to suppress oxidative stress. Apart from its anti-oxidative capacity, FGF21 activated eNOS to dilate the aorta via CaMKK2/AMPKα activation. Our data suggest expanded potential uses of FGF21 for the treatment of vascular diseases in diabetes.

scholarly journals Alterations in rat coronary vasoreactivity and vascular protein kinase C isoforms in Type 1 diabetes

2003 ◽  
Vol 285 (6) ◽  
pp. H2694-H2703 ◽  
Author(s):  
M. M. Tickerhoof ◽  
P A. Farrell ◽  
D. H. Korzick
Keyword(s):  
Signaling Pathways ◽  
Vascular Complications ◽  
Bay K 8644 ◽  
Vascular Pathology ◽  
Internal Diameter ◽  
Partial Pancreatectomy ◽  
Protein Levels ◽  
Pkc Signaling ◽  
Pkc Β

Vascular complications associated with diabetes mellitus (DM) have been linked to activation of PKC-dependent signaling pathways in both human and animal models of DM. To determine whether aberrant PKC signaling mechanisms specifically impact the coronary circulation, we assessed isolated coronary artery (CA) responses after the induction of Type 1 DM. Male Sprague-Dawley rats were subjected to partial pancreatectomy (DM; n = 23) and compared with age-matched controls (CTL; n = 19). Vasoreactivity was assessed in single CAs (∼250 μm internal diameter) after abluminal administration of the Gq-dependent vasoconstrictors endothelin (ET)-1 (10–10–10–9 M) and U-44619 (10–9–10–5 M) or the voltage-gated Ca2+ channel agonist BAY K 8644 (10–9–10–5 M) with and without the PKC inhibitor bisindolylmaleimide (Bis; 10–6 M). Dilator responses to ACh (10–9–10–5 M) were also assessed. ET-1 resulted in significantly greater constriction in the DM versus CTL group (50 ± 4% vs. 33 ± 5%, P < 0.0001), whereas responses to U-44619 and BAY K 8644 were similar between groups. Importantly, inhibition of ET-1 and U-44619 constriction by Bis occurred in the DM but not CTL group ( P < 0.05). Western blotting on isolated CAs revealed greater levels of PKC-α, PKC-βI, and PKC-βII by 22%, 15.3%, and 17.6%, respectively, in the DM versus CTL group ( P < 0.05), whereas PKC-δ and PKC-ϵ protein levels were unchanged. DM was also associated with attenuated CA dilation after ACh treatment ( P < 0.0566) and reductions in endothelial nitric oxide synthase protein levels versus CTL ( P < 0.03). These data suggest that Ca2+-dependent PKC signaling pathways, particularly for ET-1, play a greater role in modulating CA vasoconstrictor responses in DM versus CTL. These data further suggest that aberrant CA constrictor and dilator responses are likely to contribute to the coronary vascular pathology associated with DM.

scholarly journals Sodium butyrate activates NRF2 to ameliorate diabetic nephropathy possibly via inhibition of HDAC

2017 ◽  
Vol 232 (1) ◽  
pp. 71-83 ◽  
Author(s):  
Wenpeng Dong ◽  
Ye Jia ◽  
Xiuxia Liu ◽  
Huan Zhang ◽  
Tie Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Sodium Butyrate ◽  
Nuclear Translocation ◽  
Negative Regulator ◽  
Heme Oxygenase 1 ◽  
Transcriptional Level ◽  
Related Factor ◽  
Diabetic Mice ◽  
Hdac Activity

Oxidative stress contributes to the pathogenesis of diabetic nephropathy (DN). Nuclear factor erythroid 2-related factor 2 (NRF2) plays a key role in cellular defense against oxidative stress. NRF2 activators have shown promising preventive effects on DN. Sodium butyrate (NaB) is a known activator of NRF2. However, it is unknown whether NRF2 is required for NaB protection against DN. Therefore, streptozotocin-induced diabetic C57BL/6 Nrf2 knockout and their wild-type mice were treated in the presence or absence of NaB for 20 weeks. Diabetic mice, but not NaB-treated diabetic mice, developed significant renal oxidative damage, inflammation, apoptosis, fibrosis, pathological changes and albuminuria. NaB inhibited histone deacetylase (HDAC) activity and elevated the expression of Nrf2 and its downstream targets heme oxygenase 1 and NAD(P)H dehydrogenase quinone 1. Notably, deletion of the Nrf2 gene completely abolished NaB activation of NRF2 signaling and protection against diabetes-induced renal injury. Interestingly, the expression of Kelch-like ECH-associated protein 1, the negative regulator of NRF2, was not altered by NaB under both diabetic and non-diabetic conditions. Moreover, NRF2 nuclear translocation was not promoted by NaB. Therefore, the present study indicates, for the first time, that NRF2 plays a key role in NaB protection against DN. Other findings suggest that NaB may activate Nrf2 at the transcriptional level, possibly by the inhibition of HDAC activity.

scholarly journals Therapeutic Effect of MG132 on the Aortic Oxidative Damage and Inflammatory Response in OVE26 Type 1 Diabetic Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Xiao Miao ◽  
Wenpeng Cui ◽  
Weixia Sun ◽  
Ying Xin ◽  
Bo Wang ◽  
...  
Keyword(s):  
Therapeutic Effect ◽  
Chronic Treatment ◽  
Low Dose ◽  
Matched Control ◽  
Related Factor ◽  
Nuclear Factor ◽  
Diabetic Mice ◽  
Pathological Changes ◽  
Nrf2 Expression

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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