Cinnamaldehyde attenuates high glucose-induced oxidative stress and endothelial dysfunction as an Nrf2 activator

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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Abstract 14746: Dynamic SIRTUIN1-modulated Lysine Acetylation of P66shc Governs Vascular Endothelial Oxidative Stress and Dysfunction of Diabetes

Circulation ◽

10.1161/circ.130.suppl_2.14746 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Santosh Kumar ◽

Young Rae Kim ◽

Ajit Vikram ◽

Asma Naqvi ◽

Ajay Kumar ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

High Glucose ◽

Vascular Dysfunction ◽

Stress Protein ◽

Lysine Acetylation ◽

Vascular Endothelial ◽

Endothelium Dysfunction ◽

Lysine Deacetylase ◽

Oxidative Function

The SIRTUIN1 lysine deacetylase (SIRT1) ameliorates diabetic vascular dysfunction by epigenetically suppressing endothelial expression of the oxidative stress protein p66shc. However, whether SIRT1 modulates the oxidative function of p66shc by directly targeting it for lysine deacetylation is not known. Here we show that the oxidative function of p66shc is dynamically modulated by lysine acetylation. Mass spectroscopy identified lysine 81 in the unique CH2 domain of p66shc as the residue targeted by SIRT1. High glucose and SIRT1 knockdown stimulates acetylation of lysine 81 of endothelial p66shc. Compared to WT p66shc, non-acetylatable (K81R) p66shc is significantly handicapped in promoting endothelial hydrogen peroxide production stimulated by high glucose. Compared to WT p66shc, K81R p66shc is also less prone to serine 36 phosphorylation by high glucose, which is essential for the oxidative function of p66shc. Moreover, in contrast to WT p66shc which worsens endothelial dysfunction, expression of K81R p66shc does not impair endothelial function in wild type mice and rescues endothelium dysfunction of diabetic db+/db+ mouse aortas . These findings show that lysine 81 acetylation promotes the oxidative role of p66shc in hyperglycemic conditions, and is essential for p66shc-mediated endothelial dysfunction.

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The Adiponectin Receptor Agonist AdipoRon Ameliorates Diabetic Nephropathy in a Model of Type 2 Diabetes

Journal of the American Society of Nephrology ◽

10.1681/asn.2017060627 ◽

2018 ◽

Vol 29 (4) ◽

pp. 1108-1127 ◽

Cited By ~ 53

Author(s):

Yaeni Kim ◽

Ji Hee Lim ◽

Min Young Kim ◽

Eun Nim Kim ◽

Hye Eun Yoon ◽

...

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Diabetic Nephropathy ◽

Protein Kinase ◽

Endothelial Dysfunction ◽

High Glucose ◽

Receptor Agonist ◽

Intracellular Ca ◽

Intracellular Pathways

Adiponectin exerts renoprotective effects against diabetic nephropathy (DN) by activating the AMP-activated protein kinase (AMPK)/peroxisome proliferative-activated receptor–α (PPARα) pathway through adiponectin receptors (AdipoRs). AdipoRon is an orally active synthetic adiponectin receptor agonist. We investigated the expression of AdipoRs and the associated intracellular pathways in 27 patients with type 2 diabetes and examined the effects of AdipoRon on DN development in male C57BLKS/J db/db mice, glomerular endothelial cells (GECs), and podocytes. The extent of glomerulosclerosis and tubulointerstitial fibrosis correlated with renal function deterioration in human kidneys. Expression of AdipoR1, AdipoR2, and Ca2+/calmodulin-dependent protein kinase kinase–β (CaMKKβ) and numbers of phosphorylated liver kinase B1 (LKB1)– and AMPK-positive cells significantly decreased in the glomeruli of early stage human DN. AdipoRon treatment restored diabetes-induced renal alterations in db/db mice. AdipoRon exerted renoprotective effects by directly activating intrarenal AdipoR1 and AdipoR2, which increased CaMKKβ, phosphorylated Ser431LKB1, phosphorylated Thr172AMPK, and PPARα expression independently of the systemic effects of adiponectin. AdipoRon-induced improvement in diabetes-induced oxidative stress and inhibition of apoptosis in the kidneys ameliorated relevant intracellular pathways associated with lipid accumulation and endothelial dysfunction. In high-glucose–treated human GECs and murine podocytes, AdipoRon increased intracellular Ca2+ levels that activated a CaMKKβ/phosphorylated Ser431LKB1/phosphorylated Thr172AMPK/PPARα pathway and downstream signaling, thus decreasing high-glucose–induced oxidative stress and apoptosis and improving endothelial dysfunction. AdipoRon further produced cardioprotective effects through the same pathway demonstrated in the kidney. Our results show that AdipoRon ameliorates GEC and podocyte injury by activating the intracellular Ca2+/LKB1-AMPK/PPARα pathway, suggesting its efficacy for treating type 2 diabetes–associated DN.

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Discovery of polypodiside as a Keap1-dependent Nrf2 activator attenuating oxidative stress and accumulation of extracellular matrix in glomerular mesangial cells under high glucose

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2020.115833 ◽

2020 ◽

Vol 28 (24) ◽

pp. 115833

Author(s):

Huankai Yao ◽

Nan Zhang ◽

Wenting Zhang ◽

Jindong Li ◽

Huilian Hua ◽

...

Keyword(s):

Oxidative Stress ◽

Extracellular Matrix ◽

High Glucose ◽

Mesangial Cells ◽

Glomerular Mesangial Cells ◽

Nrf2 Activator

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/1714896 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 5

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.

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Role of apoptosis and oxidative stress in high glucose-induced endothelial dysfunction in isolated aortic rings

Journal of advanced Biomedical and Pharmaceutical Sciences ◽

10.21608/jabps.2021.95071.1139 ◽

2021 ◽

Vol 0 (0) ◽

pp. 23-28

Author(s):

Eman Awad ◽

Al-Shaimaa Ahmed ◽

Mahmoud El-Daly ◽

Nashwa El-Tahawy ◽

Alshaimaa Kasem ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

High Glucose ◽

And Oxidative Stress

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The Acute Oxidative Stress and High Glucose Level Synergistically Enhance Endothelial Dysfunction In Vitro

Academic Emergency Medicine ◽

10.1197/j.aem.2006.03.460 ◽

2006 ◽

Vol 13 (5Supplement 1) ◽

pp. S182-S182

Author(s):

S. Mishima

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Glucose Level ◽

High Glucose ◽

High Glucose Level

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Rhodiola crenulata Attenuates High Glucose Induced Endothelial Dysfunction in Human Umbilical Vein Endothelial Cells

The American Journal of Chinese Medicine ◽

10.1142/s0192415x17500665 ◽

2017 ◽

Vol 45 (06) ◽

pp. 1201-1216 ◽

Cited By ~ 9

Author(s):

Li-Yen Huang ◽

I-Chuan Yen ◽

Wei-Cheng Tsai ◽

Blerina Ahmetaj-Shala ◽

Tsu-Chung Chang ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Endothelial Dysfunction ◽

Cell Viability ◽

High Glucose ◽

Umbilical Vein ◽

Root Extract ◽

Human Umbilical Vein ◽

Rhodiola Crenulata ◽

Umbilical Vein Endothelial Cells

Rhodiola crenulata root extract (RCE), a traditional Chinese medicine, has been shown to regulate glucose and lipid metabolism via the AMPK pathway in high glucose (HG) conditions. However, the effect of RCE on HG-induced endothelial dysfunction remains unclear. The present study was designed to examine the effects and mechanisms of RCE against hyperglycemic insult in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were pretreated with or without RCE and then exposed to 33[Formula: see text]mM HG medium. The cell viability, nitrite production, oxidative stress markers, and vasoactive factors, as well as the mechanisms underlying RCE action, were then investigated. We found that RCE significantly improved cell death, nitric oxide (NO) defects, and oxidative stress in HG conditions. In addition, RCE significantly decreased the HG-induced vasoactive markers, including endothelin-1 (ET-1), fibronectin, and vascular endothelial growth factor (VEGF). However, the RCE-restored AMPK-Akt-eNOS-NO axis and cell viability were abolished by the presence of an AMPK inhibitor. These findings suggested that the protective effects of RCE were associated with the AMPK-Akt-eNOS-NO signaling pathway. In conclusion, we showed that RCE protected endothelial cells from hyperglycemic insult and demonstrated its potential for use as a treatment for endothelial dysfunction in diabetes mellitus.

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