Periadventitial Adipose Tissue Promotes Endothelial Dysfunction via Oxidative Stress in Diet-Induced Obese C57Bl/6 Mice

Abstract Introduction Extracellular signal-regulated kinase (ERK) modulates differentiation and maturation of adipocyte and the hypertrophy and differentiation of adipocytes affected the vascular diseases in obese. Changes in characters of adipocytes could develope the oxidative stress and inflammations. Moreover, changes in perivascular adipose tissue (PVAT) could modulate vascular tonus in obesity. However, the role of adipose ERK2 in endothelial function and characters of PVAT in obese in vivo had not been clarified, yet. Purpose This study aims to elucidate the role of the adipose ERK2 in endothelial-dependent relaxation (EDR) in mice model of obesity. The role of PVAT in EDR was also assessed. Methods and results We created adipose-specific ERK2 knock out mice (AE2KO) by crossing fatty acid binding protein 4 Cre and ERK2 flox mice and fed them with normal diet (ND) or high fat/ high sucrose diet (HFHSD) for 24 weeks. AE2KO fed with HFHSD gained more weight and revealed the heterogeneity in sizes of adipocyte in subcutaneous fat (SF). Furthermore, the mRNA levels of lipoprotein lipase, hormone-sensitive lipase, and peroxisome proliferator-activated receptor γ, which was the master genes of adipocyte differentiation, were markedly down-regulated in SF. PVAT in AE2KO with HFHSD was markedly enlarged and the mRNA expression of inflammatory adipocytokines, such as IL-1β and leptin were up-regulated. Next, we assessed EDR by acetylcholine (ACh) -induced relaxation in aortic rings with or without PVAT. EDR without PVAT was modestly decreased in AE2KO with HFHSD compared with wild type mice (WT) with HFHSD. Aortic rings with PVAT increased EDR in WT with ND. PVAT modestly decreased EDR in WT with HFHSD and mostly eliminated EDR in AE2KO with HFHSD. To assess the contraction factors released from PVAT, the solutions incubated with PVAT (SIP) were transferred to the normal aortic rings. SIP from WT with HFHSD mildly increased vascular tone and SIP from AE2KO with HFHSD further increased it. Tempol, which was superoxide scavenger, restored endothelial dysfunction with PVAT and suppressed the contraction with SIP from AE2KO with HFHSD. Fluorescence intensity of dihydroethidium stain of aorta and PVAT, which indicated that aortic and adipose superoxide production were elevated in AE2KO with HFHSD, which were mostly eliminated with tempol. Conclusions Adipose ERK2 selectively modulated differentiation in SF, suppressed the aortic oxidative stress and protected from endothelial dysfunction in obese. Moreover, adipose ERK2 suppressed the hypertrophy, inflammation, and oxidative stress of PVAT in obese. The oxidative stress with the inflammation in PVAT released vasoconstriction factors, which contributed to endothelial dysfunction in obese mice. Figure 1 Funding Acknowledgement Type of funding source: None

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Clinical aspects of reactive oxygen and nitrogen species

Biochemical Society Symposium ◽

10.1042/bss0710121 ◽

2004 ◽

Vol 71 ◽

pp. 121-133 ◽

Cited By ~ 25

Author(s):

Ascan Warnholtz ◽

Maria Wendt ◽

Michael August ◽

Thomas Münzel

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Risk Factor ◽

Endothelial Dysfunction ◽

Vascular Tissue ◽

Rapid Development ◽

Reactive Oxygen ◽

Clinical Aspects ◽

No Production ◽

Oxygen Species

Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes mellitus and chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species in endothelial and/or smooth muscle cells and the adventitia, and the subsequent decrease in vascular bioavailability of NO. Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include NAD(P)H-oxidase, xanthine oxidase and endothelial nitric oxide synthase in an uncoupled state. Recent studies indicate that endothelial dysfunction of peripheral and coronary resistance and conductance vessels represents a strong and independent risk factor for future cardiovascular events. Ways to reduce endothelial dysfunction include risk-factor modification and treatment with substances that have been shown to reduce oxidative stress and, simultaneously, to stimulate endothelial NO production, such as inhibitors of angiotensin-converting enzyme or the statins. In contrast, in conditions where increased production of reactive oxygen species, such as superoxide, in vascular tissue is established, treatment with NO, e.g. via administration of nitroglycerin, results in a rapid development of endothelial dysfunction, which may worsen the prognosis in patients with established coronary artery disease.

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Effects of empagliflozin on oxidative stress and endothelial dysfunction in STZ-induced Type 1 diabetic rat

Diabetologie und Stoffwechsel ◽

10.1055/s-0034-1375104 ◽

2014 ◽

Vol 9 (S 01) ◽

Cited By ~ 3

Author(s):

M Oelze ◽

S Kröller-Schön ◽

M Mader ◽

E Zinßius ◽

P Stamm ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Diabetic Rat

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1083 Proteomic analysis reveals increased Nrf2-mediated oxidative stress response in adipose tissue of late pregnant dairy cows during summer heat stress

Journal of Animal Science ◽

10.2527/jam2016-1083 ◽

2016 ◽

Vol 94 (suppl_5) ◽

pp. 519-520

Author(s):

M. Zachut ◽

G. Kra ◽

G. Friedlander ◽

Y. Levin

Keyword(s):

Oxidative Stress ◽

Adipose Tissue ◽

Heat Stress ◽

Stress Response ◽

Dairy Cows ◽

Proteomic Analysis ◽

Oxidative Stress Response ◽

Summer Heat

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Faculty Opinions recommendation of Crosstalk Between Oxidative Stress and Endoplasmic Reticulum (ER) Stress in Endothelial Dysfunction and Aberrant Angiogenesis Associated With Diabetes: A Focus on the Protective Roles of Heme Oxygenase (HO)-1.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.735165510.793573459 ◽

2020 ◽

Author(s):

Michael Briggs

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Endothelial Dysfunction ◽

Er Stress ◽

Heme Oxygenase

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P717Glucagon-like peptide 1 (GLP-1) improves endothelial dysfunction and vascular inflammation in polymicrobial sepsis induced by cecal ligation and puncture (CLP)

European Heart Journal ◽

10.1093/eurheartj/ehz747.0322 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

S Steven ◽

J Helmstaedter ◽

F Pawelke ◽

K Filippou ◽

K Frenies ◽

...

Keyword(s):

Oxidative Stress ◽

Clinical Trials ◽

Endothelial Dysfunction ◽

Knockout Mice ◽

Vascular Inflammation ◽

Cecal Ligation ◽

Cecal Ligation And Puncture ◽

Glucose Levels ◽

Dpp4 Inhibitor ◽

Cardioprotective Effects

Abstract Objective Sepsis causes severe hypotension, accompanied by high mortality in the setting of septic shock. LEADER, SUSTAIN-6 and other clinical trials revealed cardioprotective and anti-inflammatory properties of GLP-1 analogs like Liraglutide (Lira). We already demonstrated improved survival by amelioration of disseminated intravasal coagulation (DIC) in lipopolysaccharide (LPS)-induced endotoxemia by inhibition of the GLP-1 degrading enzyme dipeptidylpeptidase-4 (DPP-4). With the present study we aim to investigate the mechanism of protective effects of the GLP-1 analog Lira and the DPP4 inhibitor Linagliptin (Lina) in the clinically relevant sepsis model cecal ligation and puncture (CLP). Methods C57/BL6j and endothelial cell-specific GLP-1 receptor knockout mice (Cdh5crexGLP-1rfl/flmice) were used and sepsis was induced by cecal ligation and puncture (CLP). DPP4 inhibitor (Lina, 5mg/kg/d; 3 days) and GLP-1 analog (Lira, 200μg/kg/d; 3 days) were applied subcutaneously. Aortic vascular function was tested by isometric tension recording. Aorta and heart tissue was used for Western blotting, dot blot and qRT-PCR. Endogenous GLP-1 (7–36 and 9–36) and insulin was determined by ELISA. Blood samples were collected for examination of cell count, oxidative stress and glucose levels. Results Body temperature was increased by CLP and normalized by Lina and Lira. Sham- and Lira- but not Lina-treated septic mice showed low blood glucose levels compared to healthy controls. Acetylcholine-induced (endothelium-dependent) vascular relaxation in aorta was impaired by CLP. This was accompanied by vascular inflammation and elevation of IL-6, iNOS, ICAM-1, and TNF-alpha mRNA levels in aortic tissue. Vascular, cardiac and whole blood oxidative stress were increased by CLP. Furthermore, we detected higher levels of IL-6, 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-NHE) in plasma of CLP animals. Lina and Lira reduced oxidative stress and vascular inflammation, which was accompanied by improved endothelial function. In addition, CLP treatment in endothelial specific knockout mice of the GLP-1r strongly induced mortality compared to WT mice, with the effect being strongest in the Lira-treated group. Conclusion The present study demonstrates that Lina (DPP4 inhibitor) and the GLP-1 analog Lira ameliorate sepsis-induced endothelial dysfunction by reduction of vascular inflammation and oxidative stress. Clinical trials like LEADER and SUSTAIN-6 proved that GLP-1 analogs like Lira have cardioprotective effects in T2DM patients. The present study, performed in a clinically relevant model of polymicrobial sepsis, reveals that the known cardioprotective effects of GLP-1 might be translated to other diseases which affect the cardiovascular system like sepsis, underlining the potent anti-inflammatory effects of GLP-1 analogs.

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Abrogation of Toll-Like Receptor 4 Mitigates Obesity-Induced Oxidative Stress, Proinflammation, and Insulin Resistance Through Metabolic Reprogramming of Mitochondria in Adipose Tissue

Antioxidants and Redox Signaling ◽

10.1089/ars.2019.7737 ◽

2020 ◽

Vol 33 (2) ◽

pp. 66-86 ◽

Cited By ~ 2

Author(s):

Hung-Yu Lin ◽

Shao-Wen Weng ◽

Feng-Chih Shen ◽

Yen-Hsiang Chang ◽

Wei-Shiung Lian ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Adipose Tissue ◽

Metabolic Reprogramming ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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The Use of Coenzyme Q10 in Cardiovascular Diseases

Antioxidants ◽

10.3390/antiox10050755 ◽

2021 ◽

Vol 10 (5) ◽

pp. 755

Author(s):

Yoana Rabanal-Ruiz ◽

Emilio Llanos-González ◽

Francisco J. Alcain

Keyword(s):

Oxidative Stress ◽

Cardiovascular Diseases ◽

Endothelial Dysfunction ◽

Vascular System ◽

Contractile Function ◽

Artery Bypass ◽

Bypass Graft ◽

No Bioavailability ◽

Coq10 Supplementation ◽

Endogenous Antioxidant

CoQ10 is an endogenous antioxidant produced in all cells that plays an essential role in energy metabolism and antioxidant protection. CoQ10 distribution is not uniform among different organs, and the highest concentration is observed in the heart, though its levels decrease with age. Advanced age is the major risk factor for cardiovascular disease and endothelial dysfunction triggered by oxidative stress that impairs mitochondrial bioenergetic and reduces NO bioavailability, thus affecting vasodilatation. The rationale of the use of CoQ10 in cardiovascular diseases is that the loss of contractile function due to an energy depletion status in the mitochondria and reduced levels of NO for vasodilatation has been associated with low endogenous CoQ10 levels. Clinical evidence shows that CoQ10 supplementation for prolonged periods is safe, well-tolerated and significantly increases the concentration of CoQ10 in plasma up to 3–5 µg/mL. CoQ10 supplementation reduces oxidative stress and mortality from cardiovascular causes and improves clinical outcome in patients undergoing coronary artery bypass graft surgery, prevents the accumulation of oxLDL in arteries, decreases vascular stiffness and hypertension, improves endothelial dysfunction by reducing the source of ROS in the vascular system and increases the NO levels for vasodilation.

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