Abstract 15715: Dna Methylation of Genes Involved in Inflammation Correlates With Cardiometabolic Function in Morbidly Obese Adults

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Mohamed M Ali ◽  
Chandra Hassan ◽  
Mario Masrur ◽  
Francesco Bianco ◽  
Patrice Frederick ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Vascular Function ◽  
Multiple Testing ◽  
Vascular Dysfunction ◽  
Morbidly Obese ◽  
No Production ◽  
Dna Hypomethylation ◽  
Obese Adults ◽  
Downstream Target ◽  
Differentially Methylated Genes

Obesity is a major risk factor for cardiovascular disease. We previously demonstrated impaired vascular function that correlated with global DNA hypomethylation in adipose tissue (AT) isolated from obese adults (OB). Blood-detected epigenetic profiles may serve as non-invasive clinically relevant biomarkers and stand as an unexploited precision medicine reserve. Hypothesis: We hypothesized a contributing role of DNA methylation to systemic inflammation in OB subjects compared to lean controls (CON). We also explored the correlation between these methylation profiles and cardiometabolic measurements. Methods: We obtained blood and AT samples from bariatric patients (n=24; age: 36±7 yrs; BMI: 50.7±8.7 kg/m2) and CON adults (n=24; age: 36±2 yrs; BMI: 25.8±1 kg/m2). AT-isolated arterioles were tested for flow-induced dilation (FID), nitric oxide (NO) and reactive oxygen species (ROS) production. Brachial artery flow-mediated dilation (FMD) was measured via Doppler ultrasound. Promoter methylation of 94 genes involved in inflammation and autoimmunity (EpiTect Methyl II PCR Arrays) were analyzed in whole-blood DNA in relation to vascular function and cardiometabolic risk factors. Results: 70% of genes had a higher methylated fraction in CON compare to only 28% in OB subjects. After correction for multiple testing, 28 genes were significantly hypermethylated in CON compared to OB; on top of these genes are CXCL1, CXCL12, CXCL6, EGR1, HDAC4, IGF2BP2, IL12A, IL12B, and IL17RA. Ten of these genes had significantly higher mRNA in OB compared to CON indicating the functional impact of such signals on gene transcription; on top of these genes are CXCL6, TLR5, IL6ST, IL15RA, and HDAC4. Methylation % of differentially methylated genes inversely correlated with BMI, total fat %, visceral fat%, blood pressure, fasting plasma insulin, serum IL6 and CRP (C-reactive protein), arteriolar ROS, and alcohol consumption and positive correlations with lean %, HDL, plasma folate and vitamin B12, arteriolar FID and NO production, and brachial FMD. Conclusions: Our results suggest that vascular dysfunction in OB adults may be attributed to aberrant DNA methylation. A downstream target for this pathway could reside in endothelial cells resulting in vascular dysfunction

scholarly journals DNA methylation profile of genes involved in inflammation and autoimmunity correlates with vascular function in morbidly obese adults

Epigenetics ◽  
2021 ◽  
pp. 1-17
Author(s):  
Mohamed M. Ali ◽  
Dina Naquiallah ◽  
Maryam Qureshi ◽  
Mohammed Imaduddin Mirza ◽  
Chandra Hassan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Vascular Function ◽  
Methylation Profile ◽  
Morbidly Obese ◽  
Obese Adults ◽  
Dna Methylation Profile

scholarly journals Vitamin D Improves Nitric Oxide-Dependent Vasodilation in Adipose Tissue Arterioles from Bariatric Surgery Patients

Nutrients ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 2521 ◽  
Author(s):  
Abeer M. Mahmoud ◽  
Mary Szczurek ◽  
Chandra Hassan ◽  
Mario Masrur ◽  
Antonio Gangemi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vitamin D ◽  
Weight Loss ◽  
Adipose Tissue ◽  
Vitamin D Deficiency ◽  
Morbidly Obese ◽  
No Production ◽  
Obese Adults ◽  
Time Of Surgery ◽  
Post Surgery

There is a high prevalence of vitamin-D deficiency in obese individuals that could be attributed to vitamin-D sequestration in the adipose tissue. Associations between vitamin-D deficiency and unfavorable cardiometabolic outcomes were reported. However, the pathophysiological mechanisms behind these associations are yet to be established. In our previous studies, we demonstrated microvascular dysfunction in obese adults that was associated with reduced nitric oxide (NO) production. Herein, we examined the role of vitamin D in mitigating microvascular function in morbidly obese adults before and after weight loss surgery. We obtained subcutaneous (SAT) and visceral adipose tissue (VAT) biopsies from bariatric patients at the time of surgery (n = 15) and gluteal SAT samples three months post-surgery (n = 8). Flow-induced dilation (FID) and acetylcholine-induced dilation (AChID) and NO production were measured in the AT-isolated arterioles ± NO synthase inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME), hydrogen peroxide (H2O2) inhibitor, polyethylene glycol-modified catalase (PEG-CAT), or 1,25-dihydroxyvitamin D. Vitamin D improved FID, AChID, and NO production in AT-isolated arterioles at time of surgery; these effects were abolished by L-NAME but not by PEG-CAT. Vitamin-D-mediated improvements were of a higher magnitude in VAT compared to SAT arterioles. After surgery, significant improvements in FID, AChID, NO production, and NO sensitivity were observed. Vitamin-D-induced changes were of a lower magnitude compared to those from the time of surgery. In conclusion, vitamin D improved NO-dependent arteriolar vasodilation in obese adults; this effect was more significant before surgery-induced weight loss.

Vascular dysfunction in the stroke-prone spontaneously hypertensive rat is dependent on constrictor prostanoid activity and Y chromosome lineage

2018 ◽  
Vol 132 (1) ◽  
pp. 131-143 ◽  
Author(s):  
Shanzana I. Khan ◽  
Karen L. Andrews ◽  
Ann-Maree Jefferis ◽  
Garry L. Jennings ◽  
Amanda K. Sampson ◽  
...  
Keyword(s):  
Y Chromosome ◽  
Vascular Function ◽  
Disease Risk ◽  
Spontaneously Hypertensive Rat ◽  
Vascular Dysfunction ◽  
Cardiovascular Disease Risk ◽  
Spontaneously Hypertensive ◽  
Downstream Target ◽  
Hypertensive Rat ◽  
Artery Disease

Vascular dysfunction is a hallmark of hypertension and the strongest risk factor to date for coronary artery disease. As Y chromosome lineage has emerged as one of the strongest genetic predictors of cardiovascular disease risk to date, we investigated if Y chromosome lineage modulated this important facet in the stroke-prone spontaneously hypertensive rat (SHRSP) using consomic strains. Here, we show that vascular dysfunction in the SHRSP is attributable to differential cyclooxygenase (COX) activity with nitric oxide (NO) levels playing a less significant role. Measurement of prostacyclin, the most abundant product of COX in the vasculature, confirmed the augmented COX activity in the SHRSP aorta. This was accompanied by functional impairment of the vasodilatory prostacyclin (IP) receptor, while inhibition of the thromboxane (TP) receptor significantly ameliorated vascular dysfunction in the SHRSP, suggesting this is the downstream target responsible for constrictor prostanoid activity. Importantly, Y chromosome lineage was shown to modulate vascular function in the SHRSP through influencing COX activity, prostacyclin levels and IP dysfunction. Vascular dysfunction in the renal and intrarenal arteries was also found to be prostanoid and Y chromosome dependent. Interestingly, despite no apparent differences in agonist-stimulated NO levels, basal NO levels were compromised in the SHRSP aorta, which was also Y chromosome dependent. Thus, in contrast with the widely held view that COX inhibition is deleterious for the vasculature due to inhibition of the vasodilator prostacyclin, we show that COX inhibition abolishes vascular dysfunction in three distinct vascular beds, with IP dysfunction likely being a key mechanism underlying this effect. We also delineate a novel role for Y chromosome lineage in regulating vascular function through modulation of COX and basal NO levels.

scholarly journals Hyperhomocysteinemia and Low Folate and Vitamin B12 Are Associated with Vascular Dysfunction and Impaired Nitric Oxide Sensitivity in Morbidly Obese Patients

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 2014 ◽  
Author(s):  
Mohamed Haloul ◽  
Smita Jagdish Vinjamuri ◽  
Dina Naquiallah ◽  
Mohammed Imaduddin Mirza ◽  
Maryam Qureshi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Adipose Tissue ◽  
Vitamin B12 ◽  
Ex Vivo ◽  
Vascular Dysfunction ◽  
Morbidly Obese ◽  
No Production ◽  
Obese Subjects ◽  
Synthase Inhibitor ◽  
Folate And Vitamin B12

There is a high prevalence of hyperhomocysteinemia that has been linked to high cardiovascular risk in obese individuals and could be attributed to poor nutritional status of folate and vitamin B12. We sought to examine the association between blood homocysteine (Hcy) folate, and vitamin B12 levels and vascular dysfunction in morbidly obese adults using novel ex vivo flow-induced dilation (FID) measurements of isolated adipose tissue arterioles. Brachial artery flow-mediated dilation (FMD) was also measured. Subcutaneous and visceral adipose tissue biopsies were obtained from morbidly obese individuals and non-obese controls. Resistance arterioles were isolated in which FID, acetylcholine-induced dilation (AChID), and nitric oxide (NO) production were measured in the absence or presence of the NO synthase inhibitor, L-NAME, Hcy, or the superoxide dismutase mimetic, TEMPOL. Our results demonstrated that plasma Hcy concentrations were significantly higher, while folate, vitamin B12, and NO were significantly lower in obese subjects compared to controls. Hcy concentrations correlated positively with BMI, fat %, and insulin levels but not with folate or vitamin B12. Brachial and arteriolar vasodilation were lower in obese subjects, positively correlated with folate and vitamin B12, and inversely correlated with Hcy. Arteriolar NO measurements and sensitivity to L-NAME were lower in obese subjects compared to controls. Finally, Hcy incubation reduced arteriolar FID and NO sensitivity, an effect that was abolished by TEMPOL. In conclusion, these data suggest that high concentrations of plasma Hcy and low concentrations of folate and vitamin B12 could be independent predictors of vascular dysfunction in morbidly obese individuals.

scholarly journals Full-Face Mask Use during SCUBA Diving Counters Related Oxidative Stress and Endothelial Dysfunction

2022 ◽  
Vol 19 (2) ◽  
pp. 965
Author(s):  
Morgan Levenez ◽  
Kate Lambrechts ◽  
Simona Mrakic-Sposta ◽  
Alessandra Vezzoli ◽  
Peter Germonpré ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Scuba Diving ◽  
Face Mask ◽  
Redox Status ◽  
Hypoxic Exposure ◽  
No Production ◽  
Nasal Breathing ◽  
Full Face

Impaired flow mediated dilation (FMD), an index of vascular stress, is known after SCUBA diving. This is related to a dysfunction of nitric oxide (NO) availability and a disturbance of the redox status, possibly induced by hyperoxic/hyperbaric gas breathing. SCUBA diving is usually performed with a mask only covering “half face” (HF) and therefore forcing oral breathing. Nasal NO production is involved in vascular homeostasis and, as consequence, can significantly reduce NO possibly promoting vascular dysfunction. More recently, the utilization of “full-face” (FF) mask, allowing nasal breathing, became more frequent, but no reports are available describing their effects on vascular functions in comparison with HF masks. In this study we assessed and compared the effects of a standard shallow dive (20 min at 10 m) wearing either FF or a HF mask on different markers of vascular function (FMD), oxidative stress (ROS, 8-iso-PGF2α) and NO availability and metabolism (NO2, NOx and 3-NT and iNOS expression). Data from a dive breathing a hypoxic (16% O2 at depth) gas mixture with HF mask are shown allowing hyperoxic/hypoxic exposure. Our data suggest that nasal breathing might significantly reduce the occurrence of vascular dysfunction possibly due to better maintenance of NO production and bioavailability, resulting in a better ability to counter reactive oxygen and nitrogen species. Besides the obvious outcomes in terms of SCUBA diving safety, our data permit a better understanding of the effects of oxygen concentrations, either in normal conditions or as a strategy to induce selected responses in health and disease.

scholarly journals The role of tetrahydrobiopterin in inflammation and cardiovascular disease

2012 ◽  
Vol 108 (11) ◽  
pp. 832-839 ◽  
Author(s):  
Eileen McNeill ◽  
Keith Channon
Keyword(s):  
Nitric Oxide ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Cell Types ◽  
No Production ◽  
Major Site ◽  
Cellular Redox ◽  
Oxide Synthase ◽  
New Evidence

SummaryThe cofactor tetrahydrobiopterin (BH4) is required for nitric oxide (NO) production by all nitric oxide synthase (NOS) enzymes and is a key regulator of cellular redox signalling. When BH4 levels become limiting NOS enzymes become ‘uncoupled’ and produce superoxide rather than NO. Endothelial cell BH4 is required for the maintenance of vascular function through NO production, and reduced BH4 levels are associated with vascular dysfunction. Evidence increasingly points to important roles for BH4 and NOS enzymes in other vascular cell types. Leukocytes have a fundamental role in atherosclerosis, and new evidence points to a role in the control of hypertension. Leukocytes are a major site of iNOS expression, and the regulation of this isoform is another mechanism by which BH4 availability may modulate disease. This review provides an overview of BH4 control of NOS function in both endothelial cells and leukocytes in the context of vascular disease and current therapeutic evaluations.

Fetal programming of pulmonary vascular dysfunction in mice: role of epigenetic mechanisms

2011 ◽  
Vol 301 (1) ◽  
pp. H247-H252 ◽  
Author(s):  
Emrush Rexhaj ◽  
Jonathan Bloch ◽  
Pierre-Yves Jayet ◽  
Stefano F. Rimoldi ◽  
Pierre Dessen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Fetal Programming ◽  
Vascular Function ◽  
Histone Deacetylase Inhibitors ◽  
Vascular Dysfunction ◽  
Trichostatin A ◽  
Epigenetic Mechanism ◽  
Maternal Undernutrition ◽  
Underlying Mechanisms ◽  
Pulmonary Vascular Dysfunction

Insults during the fetal period predispose the offspring to systemic cardiovascular disease, but little is known about the pulmonary circulation and the underlying mechanisms. Maternal undernutrition during pregnancy may represent a model to investigate underlying mechanisms, because it is associated with systemic vascular dysfunction in the offspring in animals and humans. In rats, restrictive diet during pregnancy (RDP) increases oxidative stress in the placenta. Oxygen species are known to induce epigenetic alterations and may cross the placental barrier. We hypothesized that RDP in mice induces pulmonary vascular dysfunction in the offspring that is related to an epigenetic mechanism. To test this hypothesis, we assessed pulmonary vascular function and lung DNA methylation in offspring of RDP and in control mice at the end of a 2-wk exposure to hypoxia. We found that endothelium-dependent pulmonary artery vasodilation in vitro was impaired and hypoxia-induced pulmonary hypertension and right ventricular hypertrophy in vivo were exaggerated in offspring of RDP. This pulmonary vascular dysfunction was associated with altered lung DNA methylation. Administration of the histone deacetylase inhibitors butyrate and trichostatin A to offspring of RDP normalized pulmonary DNA methylation and vascular function. Finally, administration of the nitroxide Tempol to the mother during RDP prevented vascular dysfunction and dysmethylation in the offspring. These findings demonstrate that in mice undernutrition during gestation induces pulmonary vascular dysfunction in the offspring by an epigenetic mechanism. A similar mechanism may be involved in the fetal programming of vascular dysfunction in humans.

scholarly journals Diphlorethohydroxycarmalol Isolated from Ishige okamurae Exerts Vasodilatory Effects via Calcium Signaling and PI3K/Akt/eNOS Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1610 ◽  
Author(s):  
Yu An Lu ◽  
Yunfei Jiang ◽  
Hye-Won Yang ◽  
Jin Hwang ◽  
You-Jin Jeon ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Transgenic Zebrafish ◽  
No Production ◽  
Protective Effects ◽  
In Vivo Experiments ◽  
Vasodilatory Effect ◽  
Ishige Okamurae

Nitric oxide (NO) is released by endothelial cells in the blood vessel wall to enhance vasodilation. Marine polyphenols are known to have protective effects against vascular dysfunction and hypertension. The present study is the first to investigate how diphlorethohydroxycarmalol (DPHC) isolated from Ishige okamurae affects calcium levels, resulting in enhanced vasodilation. We examined calcium modulation with the well-known receptors, acetylcholine receptor (AchR) and vascular endothelial growth factor 2 (VEGFR2), which are related to NO formation, and further confirmed the vasodilatory effect of DPHC. We confirmed that DPHC stimulated NO production by increasing calcium levels and endothelial nitric oxide synthase (eNOS) expression. DPHC affected AchR and VEGFR2 expression, thereby influencing transient calcium intake. Specific antagonists, atropine and SU5416, were used to verify our findings. Furthermore, based on the results of in vivo experiments, we treated Tg(flk:EGFP) transgenic zebrafish with DPHC to confirm its vasodilatory effect. In conclusion, the present study showed that DPHC modulated calcium transit through AchR and VEGFR2, increasing endothelial-dependent NO production. Thus, DPHC, a natural marine component, can efficiently ameliorate cardiovascular diseases by improving vascular function.

245-LB: Aberrant DNA Methylation as a Contributor to Obesity-Associated Vascular Dysfunction

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 245-LB
Author(s):  
MOHAMED M. ALI ◽  
CHANDRA HASSAN ◽  
MARIO MASRUR ◽  
FRANCESCO BIANCO ◽  
SHANE A. PHILLIPS ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Vascular Dysfunction ◽  
Aberrant Dna Methylation

scholarly journals DNA methylome signatures of prenatal exposure to synthetic glucocorticoids in hippocampus and peripheral whole blood of female guinea pigs in early life

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Aya Sasaki ◽  
Margaret E. Eng ◽  
Abigail H. Lee ◽  
Alisa Kostaki ◽  
Stephen G. Matthews
Keyword(s):  
Dna Methylation ◽  
Whole Blood ◽  
Guinea Pigs ◽  
Critical Role ◽  
Methylation Status ◽  
Peripheral Tissues ◽  
Epigenetic Biomarkers ◽  
Differentially Methylated Genes ◽  
Increased Risk ◽  
Synthetic Glucocorticoids

AbstractSynthetic glucocorticoids (sGC) are administered to women at risk of preterm delivery, approximately 10% of all pregnancies. In animal models, offspring exposed to elevated glucocorticoids, either by administration of sGC or endogenous glucocorticoids as a result of maternal stress, show increased risk of developing behavioral, endocrine, and metabolic dysregulation. DNA methylation may play a critical role in long-lasting programming of gene regulation underlying these phenotypes. However, peripheral tissues such as blood are often the only accessible source of DNA for epigenetic analyses in humans. Here, we examined the hypothesis that prenatal sGC administration alters DNA methylation signatures in guinea pig offspring hippocampus and whole blood. We compared these signatures across the two tissue types to assess epigenetic biomarkers of common molecular pathways affected by sGC exposure. Guinea pigs were treated with sGC or saline in late gestation. Genome-wide modifications of DNA methylation were analyzed at single nucleotide resolution using reduced representation bisulfite sequencing in juvenile female offspring. Results indicate that there are tissue-specific as well as common methylation signatures of prenatal sGC exposure. Over 90% of the common methylation signatures associated with sGC exposure showed the same directionality of change in methylation. Among differentially methylated genes, 134 were modified in both hippocampus and blood, of which 61 showed methylation changes at identical CpG sites. Gene pathway analyses indicated that prenatal sGC exposure alters the methylation status of gene clusters involved in brain development. These data indicate concordance across tissues of epigenetic programming in response to alterations in glucocorticoid signaling.

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