Apple polyphenols decrease endothelial dysfunction and atherosclerosis in ApoE mice fed with chronic Western diet

A high-fat ‘western’ diet (WD), a risk factor for the development of type 2 diabetes, may cause endothelial dysfunction one of the earliest events in atherogenesis. The dipeptidyl peptidase-4 (DPP-4) inhibitors are used to lower hyperglycemia in type 2 diabetes which is also associated with endothelial dysfunction. We tested whether consumption of a WD affected endothelium-dependent relaxation (EDR) of rat mesenteric arteries (MA) and whether the DPP-4 inhibitor linagliptin (1μM) improves EDR. Wistar Hooded rats were fed a standard diet (SD, 7% total fat) or WD (21% total fat) for 10 weeks. Consumption of the WD significantly increased superoxide release from MA assayed by lucigenin chemiluminescence (WD 1210±180 counts/mg versus SD 543±156 counts/mg, n=7-8, p<0.05) and linagliptin significantly reduced the vascular superoxide release (WD+linagliptin 432±102 counts/mg, p<0.05). Acetylcholine (ACh)-induced endothelium-dependent relaxation of MA was assessed using wire myography. WD significantly reduced the sensitivity to ACh (pEC50, SD 7.72±0.08, WD, 7.32±0.05 n=8, p<0.05) and treatment with linagliptin improved endothelial function (ACh pEC50 WD+linagliptin, 7.74±0.12, n=8, p<0.05). The contribution of EDHF to ACh-induced relaxation was determined in the presence of L-NNA and ODQ to block NOS and guanylate cyclase. EDHF-mediated relaxation was improved by linagliptin (pEC50, WD 6.24±0.06, WD+linagliptin 6.95±0.12, n=4-5, p<0.05). Linagliptin also significantly improved the contribution of NO (determined in the presence of TRAM-34 + apamin to block IKCa and SKCa) to relaxation (pEC50, WD 6.50±0.13, WD+linagliptin 7.30±0.10 n=4-6, p<0.05). Linagliptin significantly reduced vascular superoxide levels and improved the contribution of both NO and EDHF to preserve endothelium-dependent relaxation in rats fed a high fat diet. DPP-4 inhibition may have effects in addition to the lowering of plasma glucose to improve vascular function in diabetes.

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Aging is Associated with Increased Susceptibility to Western Diet‐Induced Glucose Intolerance and Endothelial Dysfunction in Mice

The FASEB Journal ◽

10.1096/fasebj.22.1_supplement.1226.7 ◽

2008 ◽

Vol 22 (S1) ◽

Author(s):

Brian Joseph Folian ◽

Jessica R Durrant ◽

Melanie L Connell ◽

Molly J Russell ◽

Douglas R Seals ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Glucose Intolerance ◽

Western Diet ◽

Increased Susceptibility

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Suppression of gut dysbiosis reverses Western diet-induced vascular dysfunction

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00187.2017 ◽

2018 ◽

Vol 314 (5) ◽

pp. E468-E477 ◽

Cited By ~ 27

Author(s):

Micah L. Battson ◽

Dustin M. Lee ◽

Dillon K. Jarrell ◽

Shuofei Hou ◽

Kayl E. Ecton ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Arterial Stiffness ◽

Gut Microbiota ◽

Vascular Function ◽

Vascular Dysfunction ◽

Nuclear Factor Κb ◽

Western Diet ◽

Standard Diet ◽

Vascular Abnormalities ◽

Gut Dysbiosis

Vascular dysfunction represents a critical preclinical step in the development of cardiovascular disease. We examined the role of the gut microbiota in the development of obesity-related vascular dysfunction. Male C57BL/6J mice were fed either a standard diet (SD) ( n = 12) or Western diet (WD) ( n = 24) for 5 mo, after which time WD mice were randomized to receive either unsupplemented drinking water or water containing a broad-spectrum antibiotic cocktail (WD + Abx) ( n = 12/group) for 2 mo. Seven months of WD caused gut dysbiosis, increased arterial stiffness (SD 412.0 ± 6.0 vs. WD 458.3 ± 9.0 cm/s, P < 0.05) and endothelial dysfunction (28% decrease in max dilation, P < 0.05), and reduced l-NAME-inhibited dilation. Vascular dysfunction was accompanied by significant increases in circulating LPS-binding protein (LBP) (SD 5.26 ± 0.23 vs. WD 11 ± 0.86 µg/ml, P < 0.05) and interleukin-6 (IL-6) (SD 3.27 ± 0.25 vs. WD 7.09 ± 1.07 pg/ml, P < 0.05); aortic expression of phosphorylated nuclear factor-κB (p-NF-κB) ( P < 0.05); and perivascular adipose expression of NADPH oxidase subunit p67phox ( P < 0.05). Impairments in vascular function correlated with reductions in Bifidobacterium spp. Antibiotic treatment successfully abrogated the gut microbiota and reversed WD-induced arterial stiffness and endothelial dysfunction. These improvements were accompanied by significant reductions in LBP, IL-6, p-NF-κB, and advanced glycation end products (AGEs), and were independent from changes in body weight and glucose tolerance. These results indicate that gut dysbiosis contributes to the development of WD-induced vascular dysfunction, and identify the gut microbiota as a novel therapeutic target for obesity-related vascular abnormalities.

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Apple polyphenols decrease endothelial dysfunction and atherosclerosis after chronic Western diet in a ApoE mouse model

Archives of Cardiovascular Diseases Supplements ◽

10.1016/j.acvdsp.2018.02.013 ◽

2018 ◽

Vol 10 (2) ◽

pp. 181 ◽

Cited By ~ 1

Author(s):

G. Bolea ◽

C. Philouze ◽

M. Dubois ◽

A. Humberclaude ◽

C. Ginies ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Mouse Model ◽

Western Diet ◽

Apoe Mouse

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Time course of development of erectile dysfunction and coronary artery endothelial dysfunction in response to a western diet: influence of endothelial nitric oxide synthase uncoupling

The FASEB Journal ◽

10.1096/fasebj.26.1_supplement.866.13 ◽

2012 ◽

Vol 26 (S1) ◽

Author(s):

Justin La Favor ◽

Ethan Anderson ◽

Miranda Chaaban ◽

Robert Hickner ◽

Christopher Wingard

Keyword(s):

Nitric Oxide ◽

Erectile Dysfunction ◽

Coronary Artery ◽

Endothelial Dysfunction ◽

Nitric Oxide Synthase ◽

Endothelial Nitric Oxide Synthase ◽

Time Course ◽

Western Diet ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

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Endothelial dysfunction in small arteries and early signs of atherosclerosis in ApoE knockout rats

Scientific Reports ◽

10.1038/s41598-020-72338-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Simin Berenji Ardestani ◽

Ingrid Eftedal ◽

Michael Pedersen ◽

Per Bendix Jeppesen ◽

Rikke Nørregaard ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Endothelial Function ◽

Early Stage ◽

Western Diet ◽

Mesenteric Arteries ◽

Standard Diet ◽

Resistance Arteries ◽

Small Resistance ◽

Apoe Ko

Abstract Endothelial dysfunction is recognized as a major contributor to atherosclerosis and has been suggested to be evident far before plaque formation. Endothelial dysfunction in small resistance arteries has been suggested to initiate long before changes in conduit arteries. In this study, we address early changes in endothelial function of atherosclerosis prone rats. Male ApoE knockout (KO) rats (11- to 13-weeks-old) were subjected to either a Western or standard diet. The diet intervention continued for a period of 20–24 weeks. Endothelial function of pulmonary and mesenteric arteries was examined in vitro using an isometric myograph. We found that Western diet decreased the contribution of cyclooxygenase (COX) to control the vascular tone of both pulmonary and mesenteric arteries. These changes were associated with early stage atherosclerosis and elevated level of plasma total cholesterol, LDL and triglyceride in ApoE KO rats. Chondroid-transformed smooth muscle cells, calcifications, macrophages accumulation and foam cells were also observed in the aortic arch from ApoE KO rats fed Western diet. The ApoE KO rats are a new model to study endothelial dysfunction during the earlier stages of atherosclerosis and could help us improve preclinical drug development.

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Abstract 618: Targeted Delivery of microRNA-146a/-181b Protects Against Endothelial Dysfunction and Prevents Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.618 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Wing Tak Wong ◽

Shuangtao Ma ◽

Yu Huang ◽

Xiaoyu Tian

Keyword(s):

Endothelial Dysfunction ◽

Targeted Delivery ◽

Carotid Arteries ◽

Vascular Inflammation ◽

Developed Countries ◽

Treated Group ◽

Western Diet ◽

Systemic Delivery ◽

Vascular Regulation ◽

Angioplasty And Stenting

Objective: Atherosclerosis, which underlies most cardiovascular diseases (CVD), is a leading cause of mortality and disability in developed countries. The endothelium is an important site of vascular regulation, and its dysfunction initiates atherosclerosis and supports its progression. Current drug therapies, percutaneous angioplasty, and stenting alleviate symptoms but do not reverse atherosclerosis. Thus, more effective strategies that prevent or reverse atherosclerosis via improved endothelial function are needed. Approach: E-selectin serves as a surface marker of inflamed endothelial cells (ECs). We attempted to deliver microRNA (miR)-146a and miR-181b to inflamed endothelium covering atherosclerotic plaques with an E-selectin-targeting multistage vector (ESTA-MSV to inhibit atherosclerosis. Cy5-conjugated miR-146a and miR-181b were packaged in polyethylene glycol-polyethyleneimine (PEG/PEI) nanoparticles and then loaded into ESTA-MSV microparticles. Male apolipoprotein E-deficient mice were fed with Western diet and injected intravenously with the particles prepared as above biweekly for 12 weeks. Results: Atherosclerotic plaque size decreased with treatment of miRs packaged in ESTA-MSV but not in PEG/PEI. Moreover, vascular inflammation markers such as macrophages in aortic root lesion and expression of chemokines in aortic tissues were decreased while the vascular smooth muscle cells and collagen were increased in plaques from ESTA-MSV/miRs-treated mice compared with vehicle-treated group. Systemic delivery of miR-146a/-181b significantly improved the ACh-induced relaxation of aortas and carotid arteries and inhibited ACh-induced endothelium-dependent contraction of carotid arteries of ApoE-/- mice fed with Western diet for 12 weeks Conclusions: Our data demonstrate that the ESTA-MSV microparticle-mediated delivery of miR-146a/-181b ameliorates the endothelial dysfunction and prevents atherosclerosis.

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