Antioxidant vitamins induce angiogenesis in the normal pig kidney

The effects of chronic supplementation with antioxidant vitamins on angiogenesis are controversial. The aim of the present study was to evaluate in kidneys of normal pigs the effect of chronic supplementation with vitamins E and C, at doses that are effective in reducing oxidative stress and attenuating angiogenesis under pathological conditions. Domestic pigs were randomized to receive a 12-wk normal diet without ( n = 6) or with antioxidant vitamins supplementation (1g/day vitamin C, 100 IU·kg−1·day−1 vitamin E; n = 6). Electron beam computed tomography (CT) was used to evaluate renal cortical vascular function in vivo, and micro-CT was to assess the spatial density and average diameter of cortical microvessels (diameter <500 μm) ex vivo. Oxidative stress and expressions of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1α were evaluated in renal tissue. The effects of increasing concentrations of the same vitamins on redox status and angiogenesis were also evaluated in human umbilical vascular endothelial cells (HUVEC). Compared with normal pigs, the density of cortical transmural microvessels was significantly greater in vitamin-supplemented pigs (149.0 ± 11.7 vs. 333.8 ± 48.1 vessel/cm2, P < 0.05), whereas the cortical perfusion response to ACh was impaired. This was accompanied by a significant increase in tissue oxidative stress and levels of VEGF and HIF-1α. A low dose of antioxidant decreased, whereas a high dose increased, HUVEC oxidative stress and angiogenesis, which was partly mediated by hydrogen peroxide. Antioxidant vitamin supplementation can increase tissue oxidative redox and microvascular proliferation in the normal kidney, probably due to a biphasic effect that depends on basal redox balance.

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SUMO2 regulates vascular endothelial function and oxidative stress in mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00530.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. H1292-H1300 ◽

Cited By ~ 2

Author(s):

Young-Rae Kim ◽

Julia S. Jacobs ◽

Qiuxia Li ◽

Ravinder Reddy Gaddam ◽

Ajit Vikram ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Function ◽

Vascular Function ◽

Ex Vivo ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Vascular Endothelial ◽

Vascular Endothelial Function ◽

Density Lipoprotein Receptor ◽

Vascular Oxidative Stress

SUMOylation is a posttranslational modification of lysine residues. Modification of proteins by small ubiquitin-like modifiers (SUMO)1, -2, and -3 can achieve varied, and often unique, physiological and pathological effects. We looked for SUMO2-specific effects on vascular endothelial function. SUMO2 expression was upregulated in the aortic endothelium of hypercholesterolemic low-density lipoprotein receptor-deficient mice and was responsible for impairment of endothelium-dependent vasorelaxation in these mice. Moreover, overexpression of SUMO2 in aortas ex vivo, in cultured endothelial cells, and transgenically in the endothelium of mice increased vascular oxidative stress and impaired endothelium-dependent vasorelaxation. Conversely, inhibition of SUMO2 impaired physiological endothelium-dependent vasorelaxation in normocholesterolemic mice. These findings indicate that while endogenous SUMO2 is important in maintenance of normal endothelium-dependent vascular function, its upregulation impairs vascular homeostasis and contributes to hypercholesterolemia-induced endothelial dysfunction. NEW & NOTEWORTHY Sumoylation is known to impair vascular function; however, the role of specific SUMOs in the regulation of vascular function is not known. Using multiple complementary approaches, we show that hyper-SUMO2ylation impairs vascular endothelial function and increases vascular oxidative stress, whereas endogenous SUMO2 is essential for maintenance of normal physiological function of the vascular endothelium.

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Increased glomerular filtration rate in early metabolic syndrome is associated with renal adiposity and microvascular proliferation

AJP Renal Physiology ◽

10.1152/ajprenal.00333.2011 ◽

2011 ◽

Vol 301 (5) ◽

pp. F1078-F1087 ◽

Cited By ~ 63

Author(s):

Zilun Li ◽

John R. Woollard ◽

Shenming Wang ◽

Michael J. Korsmo ◽

Behzad Ebrahimi ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Glomerular Filtration Rate ◽

Glomerular Filtration ◽

Filtration Rate ◽

Ex Vivo ◽

Kidney Tissue ◽

Spatial Density ◽

Bold Mri ◽

Microvascular Proliferation

Metabolic syndrome (MetS) is associated with glomerular hyperfiltration and is a risk factor for chronic kidney disease, but the underlying mechanisms are poorly defined. This study tested the hypothesis that increased glomerular filtration rate (GFR) in early MetS is associated with renal adiposity and microvascular proliferation. Twelve MetS-prone Ossabaw pigs were randomized to 10 wk of a standard (lean, n = 6) or atherogenic (MetS, n = 6) diet. Kidney hemodynamics and function, perirenal fat volume, and tubular dynamics were assessed in vivo by multidetector computed tomography (CT) and blood oxygen level-dependent (BOLD)-MRI. Microvascular architecture was assessed ex vivo with micro-CT. Candidate injury mechanisms were evaluated in kidney tissue by Western blotting and histology. Basal GFR, renal blood flow, and renal cortical perfusion and volume were elevated in the MetS group. Perirenal and kidney tissue fat, proximal-nephron intratubular fluid concentration, and endothelial nitric oxide synthase expression were increased in MetS. GFR levels correlated with tissue triglyceride levels. Elevated spatial density of 20- to 40-μm cortical microvessels was accompanied by mild oxidative stress, inflammation, and with proximal tubular vacuolization. Medullary size and perfusion were relatively preserved, and BOLD-MRI showed intact medullary tubular response to furosemide. Increased GFR in early MetS is associated with renal adiposity and microvascular proliferation, which involve mainly the renal cortex and precede significant activation of oxidative stress and inflammation. Renal adiposity and proliferative microvessels may represent novel therapeutic targets for preserving renal function in early MetS.

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Coptisine Attenuates Diabetes—Associated Endothelial Dysfunction through Inhibition of Endoplasmic Reticulum Stress and Oxidative Stress

Molecules ◽

10.3390/molecules26144210 ◽

2021 ◽

Vol 26 (14) ◽

pp. 4210

Author(s):

Yan Zhou ◽

Chunxiu Zhou ◽

Xutao Zhang ◽

Chi Teng Vong ◽

Yitao Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Risk Factors ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Vascular Function ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Ex Vivo ◽

Diabetic Mice ◽

And Oxidative Stress

Coptisine is the major bioactive protoberberine alkaloid found in Rhizoma Coptidis. Coptisine reduces inflammatory responses and improves glucose tolerance; nevertheless, whether coptisine has vasoprotective effect in diabetes is not fully characterized. Conduit arteries including aortas and carotid arteries were obtained from male C57BL/6J mice for ex vivo treatment with risk factors (high glucose or tunicamycin) and coptisine. Some arterial rings were obtained from diabetic mice, which were induced by high-fat diet (45% kcal% fat) feeding for 6 weeks combined with a low-dose intraperitoneal injection of streptozotocin (120 mg/kg). Functional studies showed that coptisine protected endothelium-dependent relaxation in aortas against risk factors and from diabetic mice. Coptisine increased phosphorylations of AMPK and eNOS and downregulated the endoplasmic reticulum (ER) stress markers as determined by Western blotting. Coptisine elevates NO bioavailability and decreases reactive oxygen species level. The results indicate that coptisine improves vascular function in diabetes through suppression of ER stress and oxidative stress, implying the therapeutic potential of coptisine to treat diabetic vasculopathy.

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The Effects of a 6-Month Omega Fatty Acid and Antioxidant Vitamin Supplementation on Functional Capacity and Cognitive Function in Older Adults with Cognitive Impairment

Proceedings ◽

10.3390/proceedings2019025036 ◽

2019 ◽

Vol 25 (1) ◽

pp. 36

Author(s):

Stavrinou ◽

Andreou ◽

Aphamis ◽

Ioannou ◽

Pantzaris ◽

...

Keyword(s):

Older Adults ◽

Cognitive Impairment ◽

Fatty Acid ◽

Cognitive Function ◽

Functional Capacity ◽

Vitamin Supplementation ◽

Antioxidant Vitamin ◽

High Dose ◽

Omega 3 ◽

Omega Fatty Acid

Aim: Aging is associated with declines in functional capacity and cognitive function. The aim of the present study was to examine, for the first time, the effects of a high-dose omega-3 and omega-6 fatty acid supplementation, in combination with antioxidant vitamins, on functional capacity and cognitive function in older adults with cognitive impairment, over a 6-month period in a randomized, double-blind, placebo-controlled design. Material & Method: Thirty-six older adults with cognitive impairment (aged 79.3 ± 7.6 yrs, 22 females) were randomized to receive either a formula containing a mixture of omega-3 and omega-6 fatty acids with antioxidant vitamins or placebo for six months. Participants completed assessments of functional capacity, cognitive function, and various aspects of quality of life at baseline and following three and six months of supplementation. Functional capacity was evaluated using two sit-to-stand tests (STS-5, STS-60), the timed-up-and-go test (TUG), the 6-min walk test (6MWT), and the handgrip strength test. Cognitive function was evaluated through the Addenbrooke’s Cognitive Examination Revised (ACE-R) and the Mini Mental State Examination (MMSE), whilst health-related quality of life, sleep quality, daily sleepiness, and fatigue were assessed by specific questionnaires. A linear mixed model with a random effect for participant was used to evaluate differences in the dependent variables between the supplementation and placebo groups throughout time, whilst it was adjusted for age and education of the participants. Results: A significant interaction between supplementation and time was found on functional capacity (6MWT and STS-60; p = 0.028 and p = 0.032, respectively), cognitive function (ACER and MMSE; p < 0.001 and p = 0.011, respectively), fatigue (p < 0.001), physical health component (p = 0.007), and daily sleepiness (p = 0.007), showing a favorable improvement for the participants receiving the nutritional supplement. Conclusions: The results of the present study showed that high-dose omega fatty acid and antioxidant vitamin supplementation improves functional capacity and cognitive function in older adults with cognitive impairment. Thus, this novel approach appears promising for reducing cognitive decline and frailty in the elderly.

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Vitamin D alleviates oxidative stress in adipose tissue and mesenteric vessels from obese patients with subclinical inflammation

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2019-0340 ◽

2020 ◽

Vol 98 (2) ◽

pp. 85-92 ◽

Cited By ~ 1

Author(s):

Mihaela Ionica ◽

Oana M. Aburel ◽

Adrian Vaduva ◽

Alexandra Petrus ◽

Sonia Rațiu ◽

...

Keyword(s):

Oxidative Stress ◽

Vitamin D ◽

Adipose Tissue ◽

Vascular Function ◽

Ex Vivo ◽

Active Form ◽

Reactive Oxygen Species Generation ◽

Obese Patients ◽

Tissue Samples

Obesity is an age-independent, lifestyle-triggered, pandemic disease associated with both endothelial and visceral adipose tissue (VAT) dysfunction leading to cardiometabolic complications mediated via increased oxidative stress and persistent chronic inflammation. The purpose of the present study was to assess the oxidative stress in VAT and vascular samples and the effect of in vitro administration of vitamin D. VAT and mesenteric artery branches were harvested during abdominal surgery performed on patients referred for general surgery (n = 30) that were randomized into two subgroups: nonobese and obese. Serum levels of C-reactive protein (CRP) and vitamin D were measured. Tissue samples were treated or not with the active form of vitamin D: 1,25(OH)2D3 (100 nmol/L, 12 h). The main findings are that in obese patients, (i) a low vitamin D status was associated with increased inflammatory markers and reactive oxygen species generation in VAT and vascular samples and (ii) in vitro incubation with vitamin D alleviated oxidative stress in VAT and vascular preparations and also improved the vascular function. We report here that the serum level of vitamin D is inversely correlated with the magnitude of oxidative stress in the adipose tissue. Ex vivo treatment with active vitamin D mitigated obesity-related oxidative stress.

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Maternal Systemic Vascular Dysfunction in a Primate Model of Defective Uterine Spiral Artery Remodeling

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00613.2020 ◽

2021 ◽

Author(s):

Eugene D. Albrecht ◽

Jeffery S. Babischkin ◽

Graham W. Aberdeen ◽

Marcia G. Burch ◽

Gerald J. Pepe

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Vascular Function ◽

First Trimester ◽

Vascular Endothelial ◽

Spiral Artery ◽

Primate Model ◽

Placental Perfusion ◽

Arterial Blood ◽

Artery Remodeling

Uterine spiral artery remodeling (UAR) is essential for placental perfusion and fetal development. A defect in UAR underpins placental ischemia disorders, e.g. preeclampsia, that result in maternal systemic vascular endothelial oxidative stress and dysfunction and hypertension. We have established a model of impaired UAR by prematurely elevating maternal serum estradiol levels during the first trimester of baboon pregnancy. However, it is unknown whether this experimental paradigm is associated with maternal vascular endothelial dysfunction. Therefore, in the present study baboons were administered estradiol on days 25-59 of gestation to suppress UAR and vascular function determined in maternal skeletal muscle obtained on day 165 (term = 184 days). Maternal peripheral serum sFlt-1 levels were 3-fold higher (P <0.05) and skeletal muscle arteriolar endothelial nitric oxide synthase protein expression and luminal area, and skeletal muscle capillary density, were 30-50% lower (P < 0.01) near term in UAR suppressed baboons. Maternal skeletal muscle catalase protein levels, reflecting oxidative stress, were 75% higher (P < 0.05) and mean arterial blood pressure 28% higher (P < 0.01) in UAR defective baboons. We propose that these changes in skeletal muscle, a systemic tissue, were induced by the elevation in sFlt-1, which suppresses vascular endothelial growth factor bioavailability. In summary, maternal skeletal muscle vascular function was disrupted in a baboon model of impaired UAR. These results highlight the translational impact of this primate model and relevance to adverse conditions of human pregnancy underpinned by improper uterine artery transformation.

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Antioxidant Vitamins C and E Supplementation Does Not Improve the Hemolytic Profile of Sickle Cell Anemia Patients: A Randomized, Double-Blind, Placebo-Controlled Trial

Blood ◽

10.1182/blood.v118.21.1063.1063 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1063-1063

Author(s):

Martha Mariana A S Arruda ◽

Grazielle Mecabo ◽

Celso Arrais Rodrigues ◽

Sandra S Matsuda ◽

Iara Baldim Rabelo ◽

...

Keyword(s):

Oxidative Stress ◽

Uric Acid ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Reticulocyte Count ◽

Antioxidant Vitamins ◽

Vitamin Supplementation ◽

Indirect Bilirubin ◽

Severe Deficiency ◽

The Impact

Abstract Abstract 1063 Background: Erythrocytes of sickle cell anemia (SCA) patients continuously produce larger amounts of pro-oxidants than normal cells, and oxidative stress seems to play a significant role in the pathophysiology of this disease. In erythrocytes, oxidative stress primarily affects the membrane and results in hemolysis. The use of antioxidants in vitro reduces the generation of pro-oxidants, which could prevent adhesion and phagocytosis of oxidized erythrocytes. Aims: To evaluate the impact of antioxidant vitamins C (vitC) and E (vitE) supplementation in the hemolytic profile in SCA patients. Patients and methods: Homozygous SCA or S-β-thalassemia patients, over 18 years, were randomly assigned to receive VitC 1,400 mg + VitE 800 mg per day or placebo, administered orally for 180 days. Pregnant women and patients with iron overload out of chelation therapy were excluded. Patients were evaluated clinically and blood samples were collected at days 0 and 180 for complete blood count, automated reticulocyte count, indirect bilirubin, lactate dehydrogenase (LDH), haptoglobin, uric acid, and serum levels of VitC and VitE. Results: Overall, 83 patients were enrolled (44 vitamins, 39 placebo). The median (range) age was 27 (18–68) years, and 53 (64%) were female. There were no significant differences between the two groups as regards clinical complications of SCA or baseline laboratorial tests and serum vitC and vitE. Sixty percent of the patients were VitC deficient (30% with severe deficiency), 70% were VitE deficient (33% with severe deficiency) and 44% were deficient in both vitamins. Vitamin supplementation increased VitC from 27.2 to 62.6 μMol/L (p<0.0001) and VitE from 13.9 to 20.2 μMol/L (p<0.0001). No changes in vitC or vitE were observed in patients receiving placebo. No significant changes in hemoglobin levels, hematocrit, mean corpuscular volume were observed in either group. However, patients receiving vitamin supplementation presented a significant increase in the median reticulocyte count (from 152 to 195 ×106/μL, p=0.01), LDH (from 396 to 425 U/L, p=0.018), indirect bilirubin (from 1.45 to 1.73 mg/dL, p<0.0001), and uric acid (from 4.75 to 5.15 mg/dL, p=0.02), and a decrease in the haptoglobin levels (from 3.95 to 3.45 mg/dL, p=0.06). Conclusion: Supplementation with vitamins C and E did not improve anemia and, surprisingly, increased markers of hemolysis in patients with SCA and S-β-thalassemia. The exact mechanisms to explain our findings and their clinical significance remain to be determined. Disclosures: No relevant conflicts of interest to declare.

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Antioxidant vitamin supplementation in Crohn's disease decreases oxidative stress: a randomized controlled trial

The American Journal of Gastroenterology ◽

10.1111/j.1572-0241.2003.07226.x ◽

2003 ◽

Vol 98 (2) ◽

pp. 348-353 ◽

Cited By ~ 5

Author(s):

Elaheh Aghdassi ◽

Barbara E. Wendland ◽

A.Hillary Steinhart ◽

Stephen L. Wolman ◽

Khursheed Jeejeebhoy ◽

...

Keyword(s):

Oxidative Stress ◽

Randomized Controlled Trial ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Controlled Trial ◽

Vitamin Supplementation ◽

Antioxidant Vitamin ◽

Randomized Controlled

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Endothelial-specific CYP4A2 overexpression leads to renal injury and hypertension via increased production of 20-HETE

AJP Renal Physiology ◽

10.1152/ajprenal.00364.2009 ◽

2009 ◽

Vol 297 (4) ◽

pp. F875-F884 ◽

Cited By ~ 38

Author(s):

Kazuyoshi Inoue ◽

Komal Sodhi ◽

Nitin Puri ◽

Katherine H. Gotlinger ◽

Jiang Cao ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Endothelial Dysfunction ◽

Renal Injury ◽

Vascular Function ◽

Vascular Endothelial ◽

Sprague Dawley ◽

Sd Rats ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

We have previously reported that adenoviral-mediated delivery of cytochrome P-450 (CYP) 4A2, which catalyzes the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), results in endothelial dysfunction and hypertension in Sprague-Dawley (SD) rats (Wang JS, Singh H, Zhang F, Ishizuka T, Deng H, Kemp R, Wolin MS, Hintze TH, Abraham NG, Nasjletti A, Laniado-Schwartzman M. Circ Res 98: 962–969, 2006). In this study, we targeted the vascular endothelium by using a lentivirus construct expressing CYP4A2 under the control of the endothelium-specific promoter VE-cadherin (VECAD-4A2) and examined the effect of long-term CYP4A2 overexpression on blood pressure and kidney function in SD rats. A bolus injection of VECAD-4A2 increased blood pressure ( P < 0.001) by 26, 36, and 30 mmHg 10, 20, and 30 days postinjection, respectively. Arteries from VECAD-4A2-transduced rats produced increased levels of 20-HETE ( P < 0.01), expressed lower levels of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (p-eNOS) ( P < 0.05), generated higher levels of superoxide anion, and displayed decreased relaxing responsiveness to acetylcholine ( P < 0.05). Proteinuria increased by twofold in VECAD-4A2-transduced rats compared with controls. Treatment of VECAD-4A2-transduced rats with HET0016, an inhibitor of 20-HETE biosynthesis, not only attenuated the increase in blood pressure ( P < 0.05) but also improved vascular function (acetylcholine-induced relaxations) and reduced plasma creatinine and proteinuria. HET0016 treatment decreased oxidative stress and increased the phosphorylated state of key proteins that regulate endothelial function, including eNOS, AKT, and AMPK. Collectively, these findings demonstrate that augmentation of vascular endothelial 20-HETE levels results in hypertension, endothelial dysfunction, and renal injury, which is offset by HET0016 through a reduction in vascular 20-HETE coupled with a lessening of oxidative stress and the amplification of pAKT, pAMPK, and p-eNOS levels leading to normalization of endothelial responses.

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