scholarly journals VDR Agonist Prevents Diabetic Endothelial Dysfunction through Inhibition of Prolyl Isomerase-1-Mediated Mitochondrial Oxidative Stress and Inflammation

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Meijin Zhang ◽  
Liming Lin ◽  
Changsheng Xu ◽  
Dajun Chai ◽  
Feng Peng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Protein Expression ◽  
High Glucose ◽  
Diabetic Mice ◽  
Prolyl Isomerase ◽  
Mitochondrial Oxidative Stress ◽  
Endothelial Apoptosis ◽  
Pin1 Protein ◽  
Expression And Activity

Background and aim. Upregulation of prolyl isomerase-1 (Pin1) protein expression and activity was associated with the pathogenesis of diabetic vasculopathy through induction of endothelial oxidative stress and inflammation. Moreover, VDR agonist protects against high glucose-induced endothelial apoptosis through the inhibition of oxidative stress. We aimed to explore the effects of the VDR agonist on diabetes-associated endothelial dysfunction and the role of Pin1 in this process. Methods. Streptozocin-induced diabetic mice were randomly treated with vehicle, VDR agonist (10 μg/kg/d, i.g., twice a week), or Pin1 inhibitor, Juglone (1 mg/kg/d, i.p., every other day), for eight weeks. In parallel, human umbilical vein endothelial cells (HUVECs) exposed to high-glucose condition were treated with 1,25-dihydroxyvitamin D3 and Juglone or vehicle for 72 hours. Organ chamber experiments were performed to assess endothelium-dependent relaxation to acetylcholine. Circulatory levels of Pin1, SOD, MDA, IL-1β, IL-6, and NO in diabetic mice, Pin1 protein expression and activity, subcellular distribution of p66Shc, and NF-κB p65 in high glucose-cultured HUVECs were determined. Results. Both VDR agonist and Juglone significantly improved diabetes-associated endothelial dysfunction and reduced high glucose-induced endothelial apoptosis. Mechanistically, the circulatory levels of SOD and NO were increased compared with those of vehicle-treated diabetic mice. Additionally, Pin1 protein expression and activity, p66Shc mitochondrial translocation, and NF-κB p65 in high glucose-cultured HUVECs were also inhibited by VDR agonist and Juglone. Knockdown of VDR abolished the inhibitory effects of VDR agonist on high glucose-induced upregulation of Pin1 protein expression and activity. Conclusions. VDR agonist prevents diabetic endothelial dysfunction through inhibition of Pin1-mediated mitochondrial oxidative stress and inflammation.

scholarly journals Exercise training improves endothelial function via adiponectin-dependent and independent pathways in type 2 diabetic mice

2011 ◽  
Vol 301 (2) ◽  
pp. H306-H314 ◽  
Author(s):  
Sewon Lee ◽  
Yoonjung Park ◽  
Kevin C. Dellsperger ◽  
Cuihua Zhang
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Exercise Training ◽  
Endothelial Function ◽  
Protein Expression ◽  
Diabetic Mice ◽  
Ifn Γ ◽  
And Oxidative Stress ◽  
Type 2 Diabetic

Type 2 diabetes (T2D) is a leading risk factor for a variety of cardiovascular diseases including coronary heart disease and atherosclerosis. Exercise training (ET) has a beneficial effect on these disorders, but the basis for this effect is not fully understood. This study was designed to investigate whether the ET abates endothelial dysfunction in the aorta in T2D. Heterozygous controls (m Lepr db) and type 2 diabetic mice ( db/db; Lepr db) were either exercise entrained by forced treadmill exercise or remained sedentary for 10 wk. Ex vivo functional assessment of aortic rings showed that ET restored acetylcholine-induced endothelial-dependent vasodilation of diabetic mice. Although the protein expression of endothelial nitric oxide synthase did not increase, ET reduced both IFN-γ and superoxide production by inhibiting gp91phox protein levels. In addition, ET increased the expression of adiponectin (APN) and the antioxidant enzyme, SOD-1. To investigate whether these beneficial effects of ET are APN dependent, we used adiponectin knockout (APNKO) mice. Indeed, impaired endothelial-dependent vasodilation occurred in APNKO mice, suggesting that APN plays a central role in prevention of endothelial dysfunction. APNKO mice also showed increased protein expression of IFN-γ, gp91phox, and nitrotyrosine but protein expression of SOD-1 and -3 were comparable between wild-type and APNKO. These findings in the aorta imply that APN suppresses inflammation and oxidative stress in the aorta, but not SOD-1 and -3. Thus ET improves endothelial function in the aorta in T2D via both APN-dependent and independent pathways. This improvement is due to the effects of ET in inhibiting inflammation and oxidative stress (APN-dependent) as well as in improving antioxidant enzyme (APN-independent) performance in T2D.

Long noncoding RNA OIP5-AS1 overexpression promotes viability and inhibits high glucose-induced oxidative stress of cardiomyocytes by targeting microRNA-34a/SIRT1 axis in diabetic cardiomyopathy

2020 ◽  
Vol 21 ◽  
Author(s):  
Haiyun Sun ◽  
Chong Wang ◽  
Ying Zhou ◽  
Xingbo Cheng
Keyword(s):  
Oxidative Stress ◽  
Protein Expression ◽  
Diabetic Cardiomyopathy ◽  
High Glucose ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Luciferase Reporter ◽  
H9c2 Cells ◽  
Promoting Effect

Objective: Diabetic cardiomyopathy (DCM) is an important complication of diabetes. This study was attempted to discover the effects of long noncoding RNA OIP5-AS1 (OIP5-AS1) on the viability and oxidative stress of cardiomyocyte in DCM. Methods: The expression of OIP5-AS1 and microRNA-34a (miR-34a) in DCM was detected by qRT-PCR. In vitro, DCM was simulated by high glucose (HG, 30 mM) treatment in H9c2 cells. The viability of HG (30 mM)-treated H9c2 cells was examined by MTT assay. The reactive oxygen species (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA) levels were used to evaluate the oxidative stress of HG (30 mM)-treated H9c2 cells. Dual-luciferase reporter assay was used to confirm the interactions among OIP5-AS1, miR-34a and SIRT1. Western blot was applied to analyze the protein expression of SIRT1. Results: The expression of OIP5-AS1 was down-regulated in DCM, but miR-34a was up-regulated. The functional experiment stated that OIP5-AS1 overexpression increased the viability and SOD level, while decreased the ROS and MDA levels in HG (30 mM)-treated H9c2 cells. The mechanical experiment confirmed that OIP5-AS1 and SIRT1 were both targeted by miR-34a with the complementary binding sites at 3′UTR. MiR-34a overexpression inhibited the protein expression of SIRT1. In the feedback experiments, miR-34a overexpression or SIRT1 inhibition weakened the promoting effect on viability, and mitigated the reduction effect on oxidative stress caused by OIP5-AS1 overexpression in HG (30 mM)-treated H9c2 cells. Conclusions: OIP5-AS1 overexpression enhanced viability and attenuated oxidative stress of cardiomyocyte via regulating miR-34a/SIRT1 axis in DCM, providing a new therapeutic target for DCM.

Abstract 890: Feed-forward Signaling of TNF alpha and NFkappa B Produces Endothelial Dysfunction in Coronary Arterioles In Type Ii Diabetic Mice.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jiyeon Yang ◽  
Xiangbin Xu ◽  
Glen A Laine ◽  
Cuihua Zhang
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Nuclear Factor Κb ◽  
Inhibitory Effect ◽  
Type Ii ◽  
Diabetic Mice ◽  
Necrosis Factor Alpha ◽  
Paramagnetic Resonance ◽  
Feed Forward ◽  
Coronary Arterioles

Nuclear factor-κB (NFκB) signaling reportedly increases tumor necrosis factor-alpha (TNF expression), and the oxidative stress induced by TNF may then lead to further increase NFκB expression, i.e., a feed-forward interaction. Accordingly, we hypothesized that this feed-forward interaction between TNF and NFκB may amplify one another toward the evolution of vascular disease in diabetes. To test this hypothesis, we assessed the role of NFκB in endothelial dysfunction in Lepr db mice by evaluation of endothelial function of isolated coronary resistance vessels of m Lepr db (heterozygote, normal) and Lepr db (homozygote, diabetic) mice. Coronary arterioles (40 –100 μm) were isolated and pressurized (60 cmH2O) without flow. Although dilation of vessels to the endothelium-independent vasodilator, sodium nitroprusside (SNP) was not different between Lepr db and m Lepr db mice (n = 6), dilation to the endothelium-dependent agonist, acetycholine (ACh) was reduced (n = 5, P < 0.05). Electron Paramagnetic Resonance (EPR) results show that superoxide production was reduced by NFκB antagonist (MG-132), or anti-TNF in Lepr db mice suggesting that NFκB and TNF were contributing to elevated oxidative stress. MG-132 (1 μM, n = 4) antagonized the inhibitory effect of Lepr db mice on ACh-induced dilation vs. Lepr db without treatment, but did not affect dilation in m Lepr db mice. To better understand the basis for enhanced contributions of TNF and NFκB in diabetes, we used Western analysis to assess expression of major proteins involved in TNF-mediated signaling. Previous studies have provided compelling evidence that IKK beta plays an essential role in NFκB activation in response to TNF, whereas IKK alpha appears to play a lesser role; therefore, we examined the expression levels of IKK alpha and IKK beta mRNA and protein in Lepr db null for TNF. The protein concentration and mRNA expression level of IKK alpha were increased in Lepr db mice null for TNF (db TNF- /db TNF- ) mice. One intriguing finding of this study is that the roles of IKK alpha and IKK beta appear reversed in the inflammatory response in diabetic Lepr db mice. Furthermore, our results indicate that NFκB and TNF signaling interact to amplify the oxidative stress and induce endothelial dysfunction in type II diabetes.

P0983INHIBITION OF ATF3 BY RAF INHIBITOR GW5074 ON DIABETIC NEPHROPATHY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Jee Young Han ◽  
Jin Joo Cha ◽  
Young Sun Kang ◽  
Jung Yeon Ghee ◽  
Ji Ae Yoo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Diabetic Nephropathy ◽  
High Glucose ◽  
Kinase Inhibitor ◽  
Protective Role ◽  
Activating Transcription Factor 3 ◽  
Diabetic Mice ◽  
Mice Model ◽  
Gene Expressions

Abstract Background and Aims Activating Transcription Factor 3 (ATF3) is a stress-adaptive transcription factor, which has been suggested to be involved in maintaining glucose homeostasis. ATF3 respond rapidly to various stimuli like high glucose, fatty acids and oxidative stress, and is observed to either protective or detrimental effects in diabetic condition. Therefore to elucidate the exact role in diabetic nephropathy of ATF3, we investigated the role of ATF3 by inhibition with Raf-inhibitor GW5047 on diabetic mice model. Method ATF3 level was examined in the mouse podocytes and NRK cells with either overexpression or downregulation with ATF3. 8 week db/m and db/db mice as the model of diabetic mice were examined for the expression of ATF3 and were treated with GW5074, a Raf1 kinase inhibitor targeting the ATF3 intraperitoneally with a dose of 0.5mg/kg for 12 weeks. Results In cultured mouse podocytes and NRK cells, high glucose and angiotensin II markedly increased ATF3 expression. Gene Expressions of NOX4, MCP-1 and NF-kB were augmented by ATF3, and were attenuated by ATF3 siRNA. In db/db mice, plasma ATF3 level was not different from control db/m, however the urinary ATF3 excretion was significantly higher. Treatment of GW5074 decreased urinary ATF3 excretion. After 12 week treatment, serum creatinine level was significantly lower in the treatment db/db group, with less systemic oxidative stress. There were no significant differences in body weight, whereas the food intake was decreased in GW5047 group. Overall lipid profile or HOMA-IR, HbA1c level was not different from each group. Serum adiponectin were otherwise increased in GW5074 group. Urinary excretion of albumin at 2 month of treatment decreased with urinary nephrin excretion. Trend of increased gene expression of JNK, p-38, smad2, ERK which was downregulated by GW5074 was noted. Conclusion These findings suggest that in diabetic condition, the activation of ATF3 is associated pathogenesis of diabetic nephropathy and targeting ATF3 may have a protective role in the disease progression.

scholarly journals Tobacco smoking induces cardiovascular mitochondrial oxidative stress, promotes endothelial dysfunction, and enhances hypertension

2019 ◽  
Vol 316 (3) ◽  
pp. H639-H646 ◽  
Author(s):  
Sergey Dikalov ◽  
Hana Itani ◽  
Bradley Richmond ◽  
Liaison Arslanbaeva ◽  
Aurelia Vergeade ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Cigarette Smoke ◽  
Tobacco Smoke ◽  
Tobacco Smoking ◽  
Smoke Exposure ◽  
Metabolic Reprogramming ◽  
Wild Type ◽  
Mitochondrial Oxidative Stress

Tobacco smoking is a major risk factor for cardiovascular disease and hypertension. It is associated with the oxidative stress and induces metabolic reprogramming, altering mitochondrial function. We hypothesized that cigarette smoke induces cardiovascular mitochondrial oxidative stress, which contributes to endothelial dysfunction and hypertension. To test this hypothesis, we studied whether the scavenging of mitochondrial H2O2 in transgenic mice expressing mitochondria-targeted catalase (mCAT) attenuates the development of cigarette smoke/angiotensin II-induced mitochondrial oxidative stress and hypertension compared with wild-type mice. Two weeks of exposure of wild-type mice with cigarette smoke increased systolic blood pressure by 17 mmHg, which was similar to the effect of a subpresssor dose of angiotensin II (0.2 mg·kg−1·day−1), leading to a moderate increase to the prehypertensive level. Cigarette smoke exposure and a low dose of angiotensin II cooperatively induced severe hypertension in wild-type mice, but the scavenging of mitochondrial H2O2 in mCAT mice completely prevented the development of hypertension. Cigarette smoke and angiotensin II cooperatively induced oxidation of cardiolipin (a specific biomarker of mitochondrial oxidative stress) in wild-type mice, which was abolished in mCAT mice. Cigarette smoke and angiotensin II impaired endothelium-dependent relaxation and induced superoxide overproduction, which was diminished in mCAT mice. To mimic the tobacco smoke exposure, we used cigarette smoke condensate, which induced mitochondrial superoxide overproduction and reduced endothelial nitric oxide (a hallmark of endothelial dysfunction in hypertension). Western blot experiments indicated that tobacco smoke and angiotensin II reduce the mitochondrial deacetylase sirtuin-3 level and cause hyperacetylation of a key mitochondrial antioxidant, SOD2, which promotes mitochondrial oxidative stress. NEW & NOTEWORTHY This work demonstrates tobacco smoking-induced mitochondrial oxidative stress, which contributes to endothelial dysfunction and development of hypertension. We suggest that the targeting of mitochondrial oxidative stress can be beneficial for treatment of pathological conditions associated with tobacco smoking, such as endothelial dysfunction, hypertension, and cardiovascular diseases. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/mitochondrial-oxidative-stress-in-smoking-and-hypertension/ .

scholarly journals Effect of High Glucose-Induced Oxidative Stress on Paraoxonase 2 Expression and Activity in Caco-2 Cells

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1616 ◽  
Author(s):  
Camilla Morresi ◽  
Laura Cianfruglia ◽  
Davide Sartini ◽  
Monia Cecati ◽  
Stefania Fumarola ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Free Radical ◽  
High Glucose ◽  
Gastrointestinal Diseases ◽  
Intestinal Cells ◽  
Glycation End Products ◽  
Radical Generation ◽  
Apoptotic Pathways ◽  
Expression And Activity

(1) Background: Hyperglycemia leads to several biochemical and physiological consequences, such as the generation of advanced glycation end products (AGEs) and reactive oxygen species (ROS), which are involved in the development of several human diseases. Intestinal cells are continuously exposed to pro-oxidants and lipid peroxidation products from ingested foods, and also to glyco-oxidative damage. It has been reported that free radical generation may be linked to the development of inflammation-related gastrointestinal diseases. (2) Methods: The effects of high glucose (HG) treatment (50 mM) were assessed in terms of free radical production, lipid peroxidation, and AGEs formation. Furthermore, the expression and the antiapoptotic and antioxidant activity of the paraoxonase-2 (PON2) enzyme in intestinal cells has been investigated. (3) Results: Caco-2 cells treated with media supplied with high glucose (HG) (50 mM) showed, with respect to physiological glucose concentration (25 mM), an increase in ROS production, lipid peroxidation, and AGEs formation. Moreover, a lower PON2 expression and activity in HG-treated cells was related to activation of the apoptotic pathways. (4) Conclusions: Our results demonstrated that high glucose concentrations triggered glyco-oxidative stress in intestinal cells; the downregulation of PON2 could result in a higher oxidative stress and might contribute to intestinal dysfunction.

scholarly journals Effect of ALDH2 on High Glucose-Induced Cardiac Fibroblast Oxidative Stress, Apoptosis, and Fibrosis

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Xiaoyu Gu ◽  
Tingting Fang ◽  
Pinfang Kang ◽  
Junfeng Hu ◽  
Ying Yu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Expression ◽  
High Glucose ◽  
Collagen Type ◽  
Cardiac Fibroblasts ◽  
Collagen Type I ◽  
Cardiac Fibroblast ◽  
Type I ◽  
Mrna Levels ◽  
Neonate Rat

Our study aimed firstly to observe whether ALDH2 was expressed in neonate rat cardiac fibroblasts, then to investigate the effect of activation of ALDH2 on oxidative stress, apoptosis, and fibrosis when cardiac fibroblasts were subjected to high glucose intervention. Cultured cardiac fibroblasts were randomly divided into normal (NG), NG + Alda-1, high glucose (HG), HG + Alda-1, HG + Alda-1 + daidzin, HG + daidzin, and hypertonic groups. Double-label immunofluorescence staining, RT-PCR, and Western blot revealed ALDH2 was expressed in cardiac fibroblasts. Compared with NG, ALDH2 activity and protein expression were reduced, and cardiac fibroblast proliferation, ROS releasing, 4-HNE protein expression, collagen type I and III at mRNA levels, and the apoptosis rate were increased in HG group. While in HG + Alda-1 group, with the increases of ALDH2 activity and protein expression, the cardiac fibroblast proliferation and ROS releasing were decreased, and 4-HNE protein expression, collagen type I and III at mRNA levels, and apoptosis rate were reduced compared with HG group. When treated with daidzin in HG + Alda-1 group, the protective effects were inhibited. Our findings suggested that ALDH2 is expressed in neonate rat cardiac fibroblasts; activation of ALDH2 decreases the HG-induced apoptosis and fibrosis through inhibition of oxidative stress.

scholarly journals Ellagic Acid Reduces High Glucose-Induced Vascular Oxidative Stress Through ERK1/2/NOX4 Signaling Pathway

2017 ◽  
Vol 44 (3) ◽  
pp. 1174-1187 ◽  
Author(s):  
Artur Rozentsvit ◽  
Kevin Vinokur ◽  
Sherin Samuel ◽  
Ying Li ◽  
A. Martin Gerdes ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Protective Effect ◽  
High Glucose ◽  
Ellagic Acid ◽  
Biological Activities ◽  
Radical Scavenging ◽  
Vascular Complications ◽  
Ros Production ◽  
Gene And Protein Expression

Background/Aims: Elevated production of reactive oxygen species (ROS) is linked to endothelial dysfunction and is one of the key contributors to the pathogenesis of diabetic vascular complications. Emerging evidence has indicated that ellagic acid (EA), a polyphenol found in fruits and nuts, possesses numerous biological activities including radical scavenging. However, whether EA exerts a vasculo-protective effect via antioxidant mechanisms in blood vessels exposed to diabetic conditions remains unknown. Accordingly, the goal of this current study was to determine whether EA decreases vascular ROS production and thus ameliorates endothelial dysfunction in the diabetic milieu. Methods: Intact rat aortas and human aortic endothelial cells (HAEC) were stimulated with 30mM high glucose (HG) with and without EA co-treatment. Endothelium-dependent vasodilation was measured using a wire myograph. Gene and protein expression of non-phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 4 (NOX4) were detected using RT-PCR and western blotting, respectively. Oxidative stress was determined by measuring ROS levels using dihydroethidium (DHE) staining. Results: Intact aortas exposed to HG condition displayed exacerbated ROS production and impairment of endothelium-dependent vasodilation, characterizing endothelial dysfunction. These effects were markedly reduced with EA treatment. HG enhanced ROS production in HAEC, paralleled by increased ERK1/2 activation and NOX4 expression. EA treatment blunted the increase of ROS generation, ERK1/2 activation and decreased NOX4. Conclusions: EA significantly decreases endothelial ROS levels and ameliorates the impairment of vascular relaxation induced by HG. Our results suggest that EA exerts a vasculo-protective effect under diabetic conditions via an antioxidant effect that involves inhibition of ERK1/2 and downregulation of NOX4.

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