Docosahexaenoic acid improves vascular function via up-regulation of SIRT1 expression in endothelial cells

Jung, Sungyup; Kwon, Sun Kwan; Kwon, Min-A; Nagar, Harsha; Jeon, Byeong Hwa; Irani, Kaikobad; Yoon, Seok Hwa; Kim, Cuk-Seong

doi:10.1016/j.bbrc.2013.06.049

Cited by 33 publications

(30 citation statements)

References 26 publications

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“…Vascular endothelial dysfunction which occurs during CKD [ 28 ] is tightly linked to impaired NO production from eNOS [ 7 , 8 ], as a result of both reduced enzyme expression and activation [ 5 , 7 ]. n -3 PUFA increase eNOS expression in the endothelium via several direct and indirect mechanisms, including phosphorylation of AMPK [ 29 ] and upregulation of eNOS mRNA [ 30 ]; stimulation of SIRT-1 and of heat-shock protein 90 protein expression [ 31 , 32 ]; and finally eNOS translocation from caveolae to the cytosol [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Omega 3 Polyunsaturated Fatty Acids Improve Endothelial Dysfunction in Chronic Renal Failure: Role of eNOS Activation and of Oxidative Stress

et al. 2017

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Background: Endothelial dysfunction is a key vascular alteration in chronic kidney disease (CKD). Omega 3 (n-3) polyunsaturated fatty acids (PUFA) reduce vascular oxidative stress and inflammation. We investigated whether n-3 PUFA could reverse endothelial dysfunction in CKD by improving endothelial nitric oxide synthase (eNOS) function and oxidative stress. Methods: 5/6 nephrectomized male Wistar rats (CKD; n = 10) and sham operated animals (SHAM; n = 10) were treated for 6 weeks with standard diet. An additional group of CKD rats were fed an n-3 PUFA enriched diet (CKD + PUFA; n = 10). We then measured endothelium-dependent (EDD) and -independent vasodilation, markers of endothelial function and of oxidative stress in thoracic aortas. Results: Compared to SHAM, in CKD aortas EDD and eNOS expression were reduced (p < 0.05) and 3-nitrotyrosine levels were increased, while expression of NADPH oxidase subunits NOX4 and p22phox was similar. In-vitro incubation with Tiron failed to reverse endothelial dysfunction in CKD. In CKD + PUFA, EDD improved (p < 0.05) compared with CKD rats, while blockade of eNOS by L-NAME worsened EDD. These effects were accompanied by increased (p < 0.05) eNOS and reduced (p < 0.05) expression of NOX4 and 3-nitrotyrosine levels. Conclusion: Collectively, these findings indicate that n-3 PUFA improve endothelial dysfunction by restoring NO bioavailability in CKD.

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Section: Discussionmentioning

confidence: 99%

Omega 3 Polyunsaturated Fatty Acids Improve Endothelial Dysfunction in Chronic Renal Failure: Role of eNOS Activation and of Oxidative Stress

et al. 2017

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“…Consequently, its ability for antioxidant stress is enhanced because NO bioavailability is closely related to increased oxidative stress resistance [76, 77]. Consistently, NO bioavailability was also verified to be increased and was dependent on Sirt1-deacetylated eNOs after pretreatment with docosahexaenoic acid [78]. In addition to deacetylating eNOs, Sirt1 has been demonstrated to play a pivotal role in eNOs phosphorylation.…”

Section: Sirt1 Inhibits Oxidative Stressmentioning

confidence: 99%

Sirt1 Inhibits Oxidative Stress in Vascular Endothelial Cells

Zhang

Huang

Zeng

et al. 2017

Oxidative Medicine and Cellular Longevity

212

154

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The vascular endothelium is a layer of cells lining the inner surface of vessels, serving as a barrier that mediates microenvironment homeostasis. Deterioration of either the structure or function of endothelial cells (ECs) results in a variety of cardiovascular diseases. Previous studies have shown that reactive oxygen species (ROS) is a key factor that contributes to the impairment of ECs and the subsequent endothelial dysfunction. The longevity regulator Sirt1 is a NAD+-dependent deacetylase that has a potential antioxidative stress activity in vascular ECs. The mechanisms underlying the protective effects involve Sirt1/FOXOs, Sirt1/NF-κB, Sirt1/NOX, Sirt1/SOD, and Sirt1/eNOs pathways. In this review, we summarize the most recent reports in this field to recapitulate the potent mechanisms involving the protective role of Sirt1 in oxidative stress and to highlight the beneficial effects of Sirt1 on cardiovascular functions.

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“…Sirt1 plays a salutary role in the vasculature via several mechanisms including deacetylation-induced activation of eNOS 7 , inhibition of macrophage foam cell formation, and prevention of hyperglycemia-induced vascular cell senescence 8 , Caloric restriction, a well-known stimulant of Sirt1, decreases arterial blood pressure in healthy individuals and improves endothelium-dependent vasodilation in obese and overweight individuals 7 . In addition, nutritional pharmaceuticals such as docosahexaenoic acid (DHA) act via Sirt1-dependent deacetylation of eNOS to increase endothelial NO production and relax blood vessels 9 . Importantly, Sirt1 is a bona fide target of several miRNAs, including miR-34a 10 .…”

mentioning

confidence: 99%

P66Shc-Induced MicroRNA-34a Causes Diabetic Endothelial Dysfunction by Downregulating Sirtuin1

Kim

Vikram

et al. 2016

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Objective Diabetes mellitus causes vascular endothelial dysfunction and alters vascular microRNA expression. We investigated if endothelial microRNA-34a (miR-34a) leads to diabetic vascular dysfunction by targeting endothelial Sirtuin1 (Sirt1), and asked if the oxidative stress protein p66Shc governs miR-34a expression in the diabetic endothelium. Approach and Results MiR-34a is upregulated, and Sirt1down-regulated, in aortic endothelium of db/db and streptozotocin (STZ)-induced diabetic mice. Systemic administration of miR-34a inhibitor, or endothelium-specific knockout of miR-34a, prevents downregulation of aortic Sirt1 and rescues impaired endothelium-dependent aortic vasorelaxation induced by diabetes. Moreover, overexpression of Sirt1 mitigates impaired endothelium-dependent vasorelaxation caused by miR-34a mimic ex vivo. Systemic infusion of miR-34a inhibitor or genetic ablation of endothelial miR-34a prevents downregulation of endothelial Sirt1 by high glucose. MiR-34a is upregulated, Sirt1 is downregulated, and oxidative stress (H2O2) is induced in endothelial cells incubated with high glucose, or the free fatty acid palmitate in vitro. Increase of H2O2 and induction of endothelial miR-34a by high glucose or palmitate in vitro is suppressed by knockdown of p66shc. In addition, overexpression of wild-type but not redox-deficient p66Shc upregulates miR-34a in endothelial cells. P66Shc-stimulated upregulation of endothelial miR-34a is suppressed by cell-permeant antioxidants. Finally, mice with global knockdown of p66Shc are protected from diabetes-induced upregulation of miR-34a, and downregulation of Sirt1, in the endothelium. Conclusions These data show that hyperglycemia and elevated free fatty acids in the diabetic milieu recruit p66Shc to upregulate endothelial miR-34a via an oxidant-sensitive mechanism, which leads to endothelial dysfunction by targeting Sirt1.

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Docosahexaenoic acid improves vascular function via up-regulation of SIRT1 expression in endothelial cells

Cited by 33 publications

References 26 publications

Omega 3 Polyunsaturated Fatty Acids Improve Endothelial Dysfunction in Chronic Renal Failure: Role of eNOS Activation and of Oxidative Stress

Omega 3 Polyunsaturated Fatty Acids Improve Endothelial Dysfunction in Chronic Renal Failure: Role of eNOS Activation and of Oxidative Stress

Sirt1 Inhibits Oxidative Stress in Vascular Endothelial Cells

P66Shc-Induced MicroRNA-34a Causes Diabetic Endothelial Dysfunction by Downregulating Sirtuin1

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