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 Resveratrol, an activator of SIRT1, upregulates sarcoplasmic calcium ATPase and improves cardiac function in diabetic cardiomyopathy

2010 ◽  
Vol 298 (3) ◽  
pp. H833-H843 ◽  
Author(s):  
M. Sulaiman ◽  
M. J. Matta ◽  
N. R. Sunderesan ◽  
M. P. Gupta ◽  
M. Periasamy ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Diabetic Cardiomyopathy ◽  
Calcium Atpase ◽  
Dependent Manner ◽  
Protective Effects ◽  
Progressive Decline ◽  
Beneficial Effects ◽  
Protein Levels ◽  
Dose Dependent

Reduced sarcoplasmic calcium ATPase (SERCA2a) expression has been shown to play a significant role in the cardiac dysfunction in diabetic cardiomyopathy. The mechanism of SERCA2a repression is, however, not known. This study was designed to examine the effect of resveratrol (RSV), a potent activator of SIRT1, on cardiac function and SERCA2a expression in chronic type 1 diabetes. Adult male mice were injected with streptozotocin (STZ) and fed with either a regular diet or a diet enriched with RSV. STZ administration produced progressive decline in cardiac function, associated with markedly reduced SERCA2a and SIRT1 protein levels and increased collagen deposition; RSV treatment to these mice had a tremendous beneficial effect both in terms of improving SERCA2a expression and on cardiac function. In cultured cardiomyocytes, RSV restored SERCA2 promoter activity, which was otherwise highly repressed in high-glucose media. Protective effects of RSV were found to be dependent on its ability to activate Silent information regulator (SIRT) 1. In cardiomyocytes, overexpression of SIRT1 was found sufficient to activate SERCA2 promoter in a dose-dependent manner. In contrast, pretreatment of cardiomyocytes with SIRT1 antagonist, splitomycin, blocked these beneficial effects of RSV. In addition, SIRT1 knockout (+/−) mice were also found to be more sensitive to STZ-induced decline in SERCA2a mRNA. The data demonstrate that, in chronic diabetes, 1) the enzymatic activity of cardiac SIRT1 is reduced, which contributes to reduced expression of SERCA2a and 2) through activation of SIRT1, RSV enhances expression of SERCA2a and improves cardiac function.

scholarly journals Silencing of Vangl2 attenuates the inflammation promoted by Wnt5a via MAPK and NF-κB pathway in chondrocytes

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Ke Zhang ◽  
Zhuoying Li ◽  
Yunyang Lu ◽  
Linyi Xiang ◽  
Jiadong Sun ◽  
...  
Keyword(s):  
Western Blotting ◽  
Planar Cell Polarity ◽  
Type Ii Collagen ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Inflammatory Microenvironment ◽  
Functional Roles ◽  
Protein Levels ◽  
Oa Chondrocytes

Abstract Background The Wnt planar cell polarity (PCP) pathway is implicated in osteoarthritis (OA) both in animals and in humans. Van Gogh-like 2 (Vangl2) is a key PCP protein that is required for the orientation and alignment of chondrocytes in the growth plate. However, its functional roles in OA still remain undefined. Here, we explored the effects of Vangl2 on OA chondrocyte in vitro and further elucidated the molecular mechanism of silencing Vangl2 in Wnt5a-overexpressing OA chondrocytes. Methods Chondrocytes were treated with IL-1β (10 ng/mL) to simulate the inflammatory microenvironment of OA. The expression levels of Vangl2, Wnt5a, MMPs, and related proinflammatory cytokines were measured by RT-qPCR. Small interfering RNA (siRNA) of Vangl2 and the plasmid targeting Wnt5a were constructed and transfected into ATDC5 cells. Then, the functional roles of silencing Vangl2 in the OA chondrocytes were investigated by Western blotting, RT-qPCR, and immunocytochemistry (ICC). Transfected OA chondrocytes were subjected to Western blotting to analyze the relationship between Vangl2 and related signaling pathways. Results IL-1β induced the production of Vangl2, Wnt5a, and MMPs in a time-dependent manner and the significantly increased expression of Vangl2. Vangl2 silencing effectively suppressed the expression of MMP3, MMP9, MMP13, and IL-6 at both gene and protein levels and upregulated the expression of type II collagen and aggrecan. Moreover, knockdown of Vangl2 inhibited the phosphorylation of MAPK signaling molecules (P38, ERK, and JNK) and P65 in Wnt5a-overexpressing OA chondrocytes. Conclusions For the first time, we demonstrate that Vangl2 is involved in the OA process. Vangl2 silencing can notably alleviate OA progression in vitro by inhibiting the expression of MMPs and increasing the formation of the cartilage matrix and can inhibit the proinflammatory effects of Wnt5a via MAPK and NF-κB pathway. This study provides new insight into the mechanism of cartilage inflammation.

Abstract 3653: Akt3 Offers Stronger Protection than Akt1 Against Brain Injury by Differentially Promoting Mtor Protein Levels In Both In Vitro and In Vivo Stroke Models

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Rong Xie ◽  
Michelle Cheng ◽  
Mei Li ◽  
Robert Sapolsky ◽  
Heng Zhao
Keyword(s):  
Gene Transfer ◽  
Western Blotting ◽  
Ischemic Injury ◽  
Akt Pathway ◽  
Over Expression ◽  
Protein Levels ◽  
Akt Isoforms ◽  
The Brain

Background and Objective: Akt is a serine-threonine kinase that plays critical role in promoting cell survival. Akt consists of three isoforms (Akt1, 2, 3), with Akt3 predominantly expressed in the brain. Although Akt pathway has been shown to mediate neuronal survival in cerebral ischemic injury, it is unclear how these Akt isoforms contribute to neuronal protection, and whether exogenous Akt can protect the brain against ischemic injury or not. In this study, we over-expressed Akt isoforms and its downstream signaling proteins such as FKHR and PRAS40 to investigate the role of the Akt pathway along with its potential relationship with the mTOR pathway in stroke. Methods: Sprauge Dawley rats (250∼280g) were used for all studies. A lentiviral vector consists of a CMV promoter driving IRES-eGFP was used to clone an active Akt 1 and 3 (cAKt 1 and 3), dominant-negative Akt (AktDN), active FKHR (AAA FKHR), and PRAS40. Lentivirus expressing these genes were added to primary mixed cortical cultures for two days prior to oxygen glucose deprivation (OGD) (MOI=1:5). Neuronal survival was measured by LDH release. Lentivirus were stereotaxically injected into the cortex, and rats were subjected to focal ischemia induced by distal MCA occlusion combined with bilateral CCA occlusion. Western blotting and immunofluorescent confocal microscopy were used to detect the expression of Akt isoforms and other proteins in both the Akt and mTOR pathways. Results: Western blotting analysis showed that both endogenous Akt1 and 3 proteins degraded as early as 1 h after stroke, while Akt2 protein remained unchanged until 24 h after stroke. In vitro studies showed that over-expression of both constitutively active cAkt1 and cAkt3 decreased LDH release after OGD, while AktDN worsened neuronal death ( P <0.05). In vivo over-expression of cAkt1, cAkt3 and PRAS40 reduced infarct size after stroke ( P <0.01). Gene transfer of cAkt1 and 3 also promoted protein levels of pAkt (phosphorylated Akt), pPRAS40, pFKHR, pPTEN, pmTOR, but not pGSK3β. Both in vitro and in vivo studies showed that over-expression of cAkt3 resulted in a stronger protection than cAkt1 ( P <0.05). Interestingly, cAkt3 gene transfer preserved both endogenous protein levels of Akt1 and 3, whereas cAkt1 gene transfer only preserved endogenous Akt1. Furthermore, cAkt3 promoted higher pmTOR levels than cAkt1. Treatment of rapamycin, an mTOR inhibitor, blocked the protective effects of both cAkt1 and cAkt3 both in vitro and in vivo. Conclusion: Lentiviral-mediated overexpression of cAkt3 confers stronger protection than that of cAkt1, by maintaining both endogenous Akt1 and Akt3, as well as promoting higher mTOR activities after stroke.

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

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.

scholarly journals Ethanolic root extract of Rauwolfia serpentina alleviates copper induced genotoxicity and hepatic impairments in spotted snakehead fish, Channa punctatus (Bloch, 1793)

2021 ◽  
Vol 42 (6) ◽  
pp. 1433-1441
Author(s):  
S.P. Trivedi ◽  
◽  
V. Kumar ◽  
S. Singh ◽  
A. Trivedi ◽  
...  
Keyword(s):  
Liver Enzymes ◽  
Ethanolic Extract ◽  
Channa Punctatus ◽  
Root Extract ◽  
Dependent Manner ◽  
Control Groups ◽  
Group Iii ◽  
Protein Levels ◽  
Rauwolfia Serpentina ◽  
Group I

Aim: The present study was designed to evaluate the plausible efficacy of ethanolic extract of Rauwolfia serpentina to mitigate copper induced toxicity by investigating cytogenetic biomarkers, i.e., chromosome aberrations (CA) and micronucleus (MN) formation; assessment of biochemical changes in liver enzymes (SGOT, SGPT and ALP) and estimation of protein levels in a freshwater spotted snakehead fish(Channa punctatus). Methodology: The experiment was carried out in six groups, each having 15 specimens for 24, 48, 72, and 96 hr. Group I served as control. Groups II and III were maintained with 3 mg l-1 of Rauwolfia root extract and 0.4 mg l-1 of Cu2+, respectively. Groups IV, V, and VI were simultaneously co-exposed with 0.4 mg l-1 of Cu2+ and three different concentrations of Rauwolfia root extract 1, 2 and 3 mg l-1, respectively. For the genotoxicity assessment, blood and kidney tissues were used. Hepatic impairments were assessed after each exposure period. Results: A significant increase (p<0.05) in chromosomal aberrations, micronuclei frequency, activity of liver enzymes (SGOT, SGPT and ALP) and a decrease in protein level were recorded in Group III in comparison to the control. Groups co-exposed with Cu2+and Rauwolfia serpentine showed a significant (p<0.05) decrease in cytogenetic biomarkers, activity of liver enzymes and an increase in protein levels, as compared to Group III, with respect to control in a dose dependent manner. Interpretation: Thus, result of the present investigation establish the efficacy of R. serpentina root extract against Cu2+ induced toxicity in spotted snakehead (Channa punctatus).

scholarly journals Silencing of Vangl2 Attenuates the Inflammation Promoted by Wnt5a via MAPK and NF-κB Pathway in Chondrocytes.

2020 ◽  
Author(s):  
Ke Zhang ◽  
Zhuoying Li ◽  
Yunyang Lu ◽  
Linyi Xiang ◽  
Jiadong Sun ◽  
...  
Keyword(s):  
Western Blotting ◽  
Planar Cell Polarity ◽  
Type Ii Collagen ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Inflammatory Microenvironment ◽  
Functional Roles ◽  
Protein Levels ◽  
Oa Chondrocytes

Abstract Background: The Wnt planar cell polarity (PCP) pathway is implicated in osteoarthritis (OA) both in animals and in humans. Van Gogh-like 2 (Vangl2) is a key PCP protein that is required for the orientation and alignment of chondrocytes in the growth plate. However, its functional roles in OA still remain undefined. Here, we explored the effects of Vangl2 on OA chondrocyte in vitro, and further elucidated the molecular mechanism of silencing Vangl2 in Wnt5a-overexpressing OA chondrocytes.Methods: Chondrocytes were treated with IL-1β (10 ng/mL) to simulate the inflammatory microenvironment of OA. The expression levels of Vangl2, Wnt5a, MMPs, and related proinflammatory cytokines were measured by RT-qPCR. Small interfering RNA (siRNA) of Vangl2 and the plasmid targeting Wnt5a were constructed and transfected into ATDC5 cells. Then the functional roles of silencing Vangl2 in the OA chondrocytes were investigated by Western blotting, RT-qPCR, and immunocytochemistry (ICC). Transfected OA chondrocytes were subjected to Western blotting to analyze the relationship between Vangl2 and related signaling pathways. Results: IL-1β induced the production of Vangl2, Wnt5a and MMPs in a time-dependent manner and the significantly increased expression of Vangl2. Vangl2 silencing effectively suppressed the expression of MMP3, MMP9, MMP13 and IL-6 at both gene and protein levels, and upregulated the expression of type II collagen and aggrecan. Moreover, knockdown of Vangl2 inhibited the phosphorylation of MAPK signaling molecules (P38, ERK, and JNK) and P65 in Wnt5a-overexpressing OA chondrocytes.Conclusions: For the first time, we demonstrate that Vangl2 is involved in the OA process. Vangl2 silencing can notably alleviate OA progression in vitro by inhibiting the expression of MMPs and increasing the formation of the cartilage matrix, and can inhibit the proinflammatory effects of Wnt5a via MAPK and NF-κB pathway. This study provides new insight into the mechanism of cartilage inflammation.

scholarly journals The Role of Heme Oxygenase 1 in the Protective Effect of Caloric Restriction against Diabetic Cardiomyopathy

2019 ◽  
Vol 20 (10) ◽  
pp. 2427 ◽  
Author(s):  
Maayan Waldman ◽  
Vadim Nudelman ◽  
Asher Shainberg ◽  
Romy Zemel ◽  
Ran Kornwoski ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Beneficial Effect ◽  
Heme Oxygenase ◽  
Diabetic Cardiomyopathy ◽  
High Glucose ◽  
Heme Oxygenase 1 ◽  
Ros Production ◽  
Diabetic Mice ◽  
Protein Levels

Type 2 diabetes mellitus (DM2) leads to cardiomyopathy characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and interstitial fibrosis, all of which are exacerbated by angiotensin II (AT). SIRT1 and its transcriptional coactivator target PGC-1α (peroxisome proliferator-activated receptor-γ coactivator), and heme oxygenase-1 (HO-1) modulates mitochondrial biogenesis and antioxidant protection. We have previously shown the beneficial effect of caloric restriction (CR) on diabetic cardiomyopathy through intracellular signaling pathways involving the SIRT1–PGC-1α axis. In the current study, we examined the role of HO-1 in diabetic cardiomyopathy in mice subjected to CR. Methods: Cardiomyopathy was induced in obese diabetic (db/db) mice by AT infusion. Mice were either fed ad libitum or subjected to CR. In an in vitro study, the reactive oxygen species (ROS) level was determined in cardiomyocytes exposed to different glucose levels (7.5–33 mM). We examined the effects of Sn(tin)-mesoporphyrin (SnMP), which is an inhibitor of HO activity, the HO-1 inducer cobalt protoporphyrin (CoPP), and the SIRT1 inhibitor (EX-527) on diabetic cardiomyopathy. Results: Diabetic mice had low levels of HO-1 and elevated levels of the oxidative marker malondialdehyde (MDA). CR attenuated left ventricular hypertrophy (LVH), increased HO-1 levels, and decreased MDA levels. SnMP abolished the protective effects of CR and caused pronounced LVH and cardiac metabolic dysfunction represented by suppressed levels of adiponectin, SIRT1, PPARγ, PGC-1α, and increased MDA. High glucose (33 mM) increased ROS in cultured cardiomyocytes, while SnMP reduced SIRT1, PGC-1α levels, and HO activity. Similarly, SIRT1 inhibition led to a reduction in PGC-1α and HO-1 levels. CoPP increased HO-1 protein levels and activity, SIRT1, and PGC-1α levels, and decreased ROS production, suggesting a positive feedback between SIRT1 and HO-1. Conclusion: These results establish a link between SIRT1, PGC-1α, and HO-1 signaling that leads to the attenuation of ROS production and diabetic cardiomyopathy. CoPP mimicked the beneficial effect of CR, while SnMP increased oxidative stress, aggravating cardiac hypertrophy. The data suggest that increasing HO-1 levels constitutes a novel therapeutic approach to protect the diabetic heart. Brief Summary: CR attenuates cardiomyopathy, and increases HO-1, SIRT activity, and PGC-1α protein levels in diabetic mice. High glucose reduces adiponectin, SIRT1, PGC1-1α, and HO-1 levels in cardiomyocytes, resulting in oxidative stress. The pharmacological activation of HO-1 activity mimics the effect of CR, while SnMP increased oxidative stress and cardiac hypertrophy. These data suggest the critical role of HO-1 in protecting the diabetic heart.

scholarly journals Suppression of Sirtuin-1 Increases IL-6 Expression by Activation of the Akt Pathway During Allergic Asthma

2017 ◽  
Vol 43 (5) ◽  
pp. 1950-1960 ◽  
Author(s):  
Lingling Tang ◽  
Qingge Chen ◽  
Ziyu Meng ◽  
Li Sun ◽  
Linyun Zhu ◽  
...  
Keyword(s):  
Allergic Asthma ◽  
Sirtuin 1 ◽  
Akt Pathway ◽  
Epithelial Cell Line ◽  
Dependent Manner ◽  
Airway Epithelial ◽  
Mice Model ◽  
Akt Inhibitor ◽  
Akt Phosphorylation ◽  
Protein Levels

Background/Aims: A growing number of studies have demonstrated that the activity and expression level of sirtuin-1 (SIRT1) are decreased in asthma patients; however, the mechanisms underlying decreased SIRT1 expression and function are still not completely understood. Interleukin (IL)-6 plays important roles in inflammation during allergic asthma. In this study, we examined whether loss of SIRT1 activity regulated the expression of IL-6 and further verified the underlying mechanisms. Methods: The human airway epithelial cell line 16HBE was used to test the effects of the SIRT1 inhibitor (salermide) on expression of IL-6. IL-6 mRNA and protein expression were assessed with real-time polymerase chain reaction (PCR), immunochemistry, and ELISA. OVA-challenged mice were used as an asthma model to investigate the effect of SIRT1 activation on IL-6 and relative Akt phosphorylation level. Results: We found that inhibition of SIRT1 increased IL-6 mRNA and protein levels in a time-dependent manner, which was accompanied by increased Akt pathway activation in 16HBE cells. Furthermore activation of Akt showed upregulated expression of the IL-6 protein whereas Akt inhibitor, LY294002 or Akt siRNA significantly inhibited SIRT1-regulated IL-6 expression. Conversely, activation of SIRT1 inhibited Akt activation and IL-6 expression in an asthmatic mice model and 16HBE cells. Conclusion: Our results indicate the potential role of SIRT1 in regulating inflammation by modulation of IL-6 expression in an Akt-dependent manner during allergic asthma.

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.

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