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517 results on '"Graham, Delyth"'

109. Metabolomic identification of a novel pathway of blood pressure regulation involving hexadecanedioate

Author

Menni, Cristina, Graham, Delyth, Kastenmuller, Gabi, Alharbi, Nora H.J., Alsanos, Safaa Md, McBride, Martin, Mangino, Massimo, Titcombe, Philip, Shin, So-Youn, Psatha, Maria, Geisendorfer, Thomas, Huber, Anja, Peters, Annette, Wang-Sattler, Rui, Xu, Tao, Brosnan, Mary Julia, Trimmer, Jeff, Reichel, Christian, Mohney, Robert P., Soranzo, Nicole, Edwards, Mark H., Cooper, Cyrus, Church, Alistair C., Suhre, Karsten, Gieger, Christian, Dominiczak, Anna F., Spector, Tim D., Padmanabhan, Sandosh, and Valdes, Ana M.

Subjects
Adult, Male, Fatty acid synthases, hypertension, Blood Pressure, Palmitic Acids, Sodium Chloride, Rats, Inbred WKY, Norepinephrine, Fatty Acid Synthases, Hypertension, Metabolomics, Mortality, Germany, Rats, Inbred SHR, Animals, Humans, Aged, fatty acid synthases, Original Articles, Middle Aged, mortality, United Kingdom, Cross-Sectional Studies, England, Models, Animal, Blood pressure, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Carbachol, Female, Signal Transduction
Abstract

Supplemental Digital Content is available in the text., High blood pressure is a major contributor to the global burden of disease and discovering novel causal pathways of blood pressure regulation has been challenging. We tested blood pressure associations with 280 fasting blood metabolites in 3980 TwinsUK females. Survival analysis for all-cause mortality was performed on significant independent metabolites (P

Published
2015

111. Does high-density lipoprotein protect vascular function in healthy pregnancy?

Author

Sulaiman, Wan N Wan, Caslake, Muriel J, Delles, Christian, Karlsson, Helen, Mulder, Monique T, Graham, Delyth, Freeman, Dilys J, Sulaiman, Wan N Wan, Caslake, Muriel J, Delles, Christian, Karlsson, Helen, Mulder, Monique T, Graham, Delyth, and Freeman, Dilys J

Abstract

The maternal adaptation to pregnancy includes hyperlipidaemia, oxidative stress and chronic inflammation. In non-pregnant individuals, these processes are usually associated with poor vascular function. However, maternal vascular function is enhanced in pregnancy. It is not understood how this is achieved in the face of the adverse metabolic and inflammatory environment. Research into cardiovascular disease demonstrates that plasma HDL (high-density lipoprotein), by merit of its functionality rather than its plasma concentration, exerts protective effects on the vascular endothelium. HDL has vasodilatory, antioxidant, anti-thrombotic and anti-inflammatory effects, and can protect against endothelial cell damage. In pregnancy, the plasma HDL concentration starts to rise at 10 weeks of gestation, peaking at 20 weeks. The initial rise in plasma HDL occurs around the time of the establishment of the feto-placental circulation, a time when the trophoblast plugs in the maternal spiral arteries are released, generating oxidative stress. Thus there is the intriguing possibility that new HDL of improved function is synthesized around the time of the establishment of the feto-placental circulation. In obese pregnancy and, to a greater extent, in pre-eclampsia, plasma HDL levels are significantly decreased and maternal vascular function is reduced. Wire myography studies have shown an association between the plasma content of apolipoprotein AI, the major protein constituent of HDL, and blood vessel relaxation. These observations lead us to hypothesize that HDL concentration, and function, increases in pregnancy in order to protect the maternal vascular endothelium and that in pre-eclampsia this fails to occur., Funding agencies: Malaysian Ministry of Higher Education; grant EU-MASCARA from the European Commission [278249]; grant sysVASC from the European Commission [603288]

Published
2016
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112. Genomes and phenomes of a population of outbred rats and its progenitors

Author

Baud, Amelie, Guryev, Victor, Hummel, Oliver, Johannesson, Martina, Hermsen, Roel, Stridh, Pernilla, Graham, Delyth, McBride, Martin W., Foroud, Tatiana, Calderari, Sophie, Diez, Margarita, Ockinger, Johan, Beyeen, Amennai D., Gillett, Alan, Abdelmagid, Nada, Guerreiro-Cacais, Andre Ortlieb, Jagodic, Maja, Tuncel, Jonatan, Norin, Ulrika, Beattie, Elisabeth, Huynh, Ngan, Miller, William H., Koller, Daniel L., Alam, Imranul, Falak, Samreen, Osborne-Pellegrin, Mary, Martinez-Membrives, Esther, Canete, Toni, Blazquez, Gloria, Vicens-Costa, Elia, Mont-Cardona, Carme, Diaz-Moran, Sira, Tobena, Adolf, Zelenika, Diana, Saar, Kathrin, Patone, Giannino, Bauerfeind, Anja, Bihoreau, Marie-Therese, Heinig, Matthias, Lee, Young-Ae, Rintisch, Carola, Schulz, Herbert, Wheeler, David A., Worley, Kim C., Muzny, Donna M., Gibbs, Richard A., Lathrop, Mark, Lansu, Nico, Toonen, Pim, Ruzius, Frans Paul, de Bruijn, Ewary, Hauser, Heidi, Adams, David J., Keane, Thomas, Atanur, Santosh s., Aitman, Tim J., Flicek, Paul, Malinauskas, Tomas, Jones, E Yvonne, Ekman, Diana, Lopez-Aumatell, Regina, Dominiczak, Anna F., Holmdahl, Rikard, Olsson, Tomas, Gauguier, Dominique, Hubner, Norbert, Fernandez-Teruel, Alberto, Cuppen, Edwin, Mott, Richard, and Flint, Jonathan

Abstract

Finding genetic variants that contribute to phenotypic variation is one of the main challenges of modern genetics. We used an outbred population of rats (Heterogeneous Stock, HS) in a combined sequence-based and genetic mapping analysis to identify sequence variants and genes contributing to complex traits of biomedical relevance. Here we describe the sequences of the eight inbred progenitors of the HS and the variants that segregate between them. We report the genotyping of 1,407 HS rats, and the collection from 2,006 rats of 195 phenotypic measures that are relevant to models of anxiety, type 2 diabetes, hypertension and osteoporosis. We make available haplotype dosages for the 1,407 genotyped rats, since genetic mapping in the HS is best carried out by reconstructing each HS chromosome as a mosaic of the progenitor genomes. Finally, we have deposited an R object that makes it easy to incorporate our sequence data into any genetic study of HS rats. Our genetic data are available for both Rnor3.4 and Rnor5.0 rat assemblies.

Published
2014

113. A resource for the simultaneous high-resolution mapping of multiple quantitative trait loci in rats: the NIH heterogenous stock

Author

Johannesson, Martina, Lopez-Aumatell, Regina, Stridh, Pernilla, Diez, Margarita, Tuncel, Jonatan, Blazquez, Gloria, Martinez-membrives, Esther, Canete, Toni, Vicens-Costa, Elia, Graham, Delyth, Copley, Richard R., Hernandez-Pliego, Polinka, Beyeen, Amennai D., Ockinger, Johan, Fernandez-Santamaria, Cristina, Gulko, Percio S., Brenner, Max, Tobena, Olsson, Mott, Richard, Valdar, William, Redei, Eva E., Fernandez-Teruel, Alberto, and Flint, Jonathan

Subjects
Chromosome mapping -- Analysis, Quantitative trait loci -- Analysis, Rats -- Genetic aspects, Rats -- Physiological aspects, Rattus -- Genetic aspects, Rattus -- Physiological aspects, Health
Published
2009

123. Identification of a common molecular pathway in hypertensive renal damage : comparison of rat and human gene expression profiles

Author

Skogstrand, Trude, Leh, Sabine, McClure, John, Dashti, Mohammed, Iversen, Bjarne M, Graham, Delyth, McBride, Martin W, Hultström, Michael, Skogstrand, Trude, Leh, Sabine, McClure, John, Dashti, Mohammed, Iversen, Bjarne M, Graham, Delyth, McBride, Martin W, and Hultström, Michael

Abstract

BACKGROUND: There is a common structural progression in hypertensive renal damage with early arterial damage and fibrosis in the juxtamedullary cortex. METHOD: The present investigation identifies a common pathway using three-gene expression profiles from hypertensive rat models: 60-week-old spontaneously hypertensive rat (SHR), salt-loaded stroke-prone SHR (SHRSP), and the non-clipped kidney after 24 weeks of two-kidney, one-clip hypertension (2K1C). Kidney damage was scored using a specialized system. Gene-expression profiles were determined using microarrays and validated using a panel of 47 genes by quantitative real-time PCR. RESULTS: All groups showed kidney damage (SHRs: 0.32 ± 0.09 vs. Wistar-Kyoto rats: 0.06 ± 0.03; 2K1C: 0.27 ± 0.13 vs. pooled controls: 0.01 ± 0.01; SHRSP: 1.13 ± 0.14 vs. WKY: 0.04 ± 0.03; all P < 0.05). A total of 1614 genes were changed in the SHR experiment, 1323 in the SHRSP, and 576 in the 2K1C. Eighty-eight genes were similarly regulated in all three models. Gene ontology enrichment analysis identified 59 ontologies that were enriched in all three datasets. These included over-representation to extracellular matrix, response to oxidative stress, and immune system processes. Out of the 88 in-common genes, 40 could be connected in a common pathway that was compared to two gene-expression profiles from human kidneys with histologically verified fibrosis to identify a highly significant number of in-common genes that were also represented in the common genetic pathway. CONCLUSION: There is a common pathway during the development of hypertensive kidney damage in rats irrespective of model. Interestingly, large parts of this common pathway are conserved in human kidney damage, which may indicate a broader importance in the development of chronic kidney disease.

Published
2015
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124. Cd36 and the Molecular Basis of Insulin Resistance in the Stroke-Prone Spontaneously Hypertensive Rat

Author

COLLISON, MARY, GLAZIER, ANNE M., GRAHAM, DELYTH, MORTON, IAN, DOMINICZAK, MAREK H., AITMAN, TIMOTHY J., CONNELL, JOHN M. C., DOMINICZAK, ANNA F., and GOULD, GWYN W.

Subjects
Insulin resistance -- Genetic aspects, Fatty acid metabolism -- Abnormalities, Stroke (Disease) -- Risk factors, Health
Abstract

Defective Cd36 expression is thought to underlie the defective fatty acid metabolism and hypertriglyceridaemia in the spontaneously hypertensive rat (SHR), and has been linked with insulin resistance which is a [...]

Published
2000

125. Cardiac Hypertrophy Is Inhibited by a Local Pool of cAMP Regulated by Phosphodiesterase 2

Author

Zoccarato, Anna, primary, Surdo, Nicoletta C., additional, Aronsen, Jan M., additional, Fields, Laura A., additional, Mancuso, Luisa, additional, Dodoni, Giuliano, additional, Stangherlin, Alessandra, additional, Livie, Craig, additional, Jiang, He, additional, Sin, Yuan Yan, additional, Gesellchen, Frank, additional, Terrin, Anna, additional, Baillie, George S., additional, Nicklin, Stuart A., additional, Graham, Delyth, additional, Szabo-Fresnais, Nicolas, additional, Krall, Judith, additional, Vandeput, Fabrice, additional, Movsesian, Matthew, additional, Furlan, Leonardo, additional, Corsetti, Veronica, additional, Hamilton, Graham, additional, Lefkimmiatis, Konstantinos, additional, Sjaastad, Ivar, additional, and Zaccolo, Manuela, additional

Published
2015
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130. Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension

Author

Padmanabhan, Sandosh, Melander, Olle, Johnson, Toby, Di Blasio, Anna Maria, Lee, Wai K., Gentilini, Davide, Hastie, Claire E., Menni, Cristina, Monti, Maria Cristina, Delles, Christian, Laing, Stewart, Corso, Barbara, Navis, Gerjan, Kwakernaak, Arjan J., van der Harst, Pim, Bochud, Murielle, Maillard, Marc, Burnier, Michel, Hedner, Thomas, Kjeldsen, Sverre, Wahlstrand, Bjorn, Sjögren, Marketa, Fava, Cristiano, Montagnana, Martina, Danese, Elisa, Torffvit, Ole, Hedblad, Bo, Snieder, Harold, Connell, John M. C., Brown, Morris, Samani, Nilesh J., Farrall, Martin, Cesana, Giancarlo, Mancia, Giuseppe, Signorini, Stefano, Grassi, Guido, Eyheramendy, Susana, Wichmann, H. Erich, Laan, Maris, Strachan, David P., Sever, Peter, Shields, Denis Colm, Stanton, Alice, Vollenweider, Peter, Teumer, Alexander, Voelzke, Henry, Rettig, Rainer, Newton-Cheh, Christopher, Arora, Pankaj, Zhang, Feng, Soranzo, Nicole, Spector, Timothy D., Lucas, Gavin, Kathiresan, Sekar, Siscovick, David S., Luan, Jian'an, Loos, Ruth J. F., Wareham, Nicholas J., Penninx, Brenda W., Nolte, Ilja M., McBride, Martin, Miller, William H., Nicklin, Stuart A., Baker, Andrew H., Graham, Delyth, McDonald, Robert A., Pell, Jill P., Sattar, Naveed, Welsh, Paul, Munroe, Patricia, Caulfield, Mark J., Zanchetti, Alberto, and Dominiczak, Anna F.

Subjects
Urology and Nephrology, Cardiac and Cardiovascular Systems
Abstract

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 59 region of Uromodulin (UMOD; rs13333226, combined P value of 3.6x10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95% CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

Published
2010

131. Validation of Uromodulin as a Candidate Gene for Human Essential Hypertension

Author

Graham, Lesley A, Padmanabhan, Sandosh, Fraser, Niall J, Kumar, Satish, Bates, James M, Raffi, Hajamohideen S, Welsh, Paul, Beattie, Wendy, Hao, Shoujin, Leh, Sabine, Hultström, Michael, Ferreri, Nicholas R, Dominiczak, Anna F, Graham, Delyth, McBride, Martin W, Graham, Lesley A, Padmanabhan, Sandosh, Fraser, Niall J, Kumar, Satish, Bates, James M, Raffi, Hajamohideen S, Welsh, Paul, Beattie, Wendy, Hao, Shoujin, Leh, Sabine, Hultström, Michael, Ferreri, Nicholas R, Dominiczak, Anna F, Graham, Delyth, and McBride, Martin W

Abstract

A recent genome-wide association study identified a locus on chromosome 16 in the promoter region of the uromodulin (UMOD) gene that is associated with hypertension. Here, we examined the hypertension signal with functional studies in Umod knockout (KO) mice. Systolic blood pressure was significantly lower in KO versus wild-type (WT) mice under basal conditions (KO: 116.6±0.3 mm Hg versus WT: 136.2±0.4 mm Hg; P<0.0001). Administration of 2% NaCl did not alter systolic blood pressure in KO mice, whereas it increased in WT mice by ≈33%, P<0.001. The average 24-hour urinary sodium excretion in the KO was greater than that of WT mice (P<0.001). Chronic renal function curves demonstrate a leftward shift in KO mice, suggesting that the relationship between UMOD and blood pressure is affected by sodium. Creatinine clearance was increased during salt loading with 2% NaCl in the KO mice, leading to augmented filtered Na(+) excretion and further Na(+) loss. The difference in sodium uptake that exists between WT and KO strains was explored at the molecular level. Urinary tumor necrosis factor-α levels were significantly higher in KO mice compared with WT mice (P<0.0001). Stimulation of primary thick ascending limb of the loop of Henle cells with exogenous tumor necrosis factor-α caused a reduction in NKCC2A expression (P<0.001) with a concurrent rise in the levels of UMOD mRNA (P<0.001). Collectively, we demonstrate that UMOD regulates sodium uptake in the thick ascending limb of the loop of Henle by modulating the effect of tumor necrosis factor-α on NKCC2A expression, making UMOD an important determinant of blood pressure control.

Published
2014
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132. Origin of the Y Chromosome Influences Intrarenal Vascular Responsiveness to Angiotensin I and Angiotensin (1-7) in Stroke-Prone Spontaneously Hypertensive Rats

Author

Sampson, Amanda K., primary, Andrews, Karen L., additional, Graham, Delyth, additional, McBride, Martin W., additional, Head, Geoffrey A., additional, Thomas, Merlin C., additional, Chin-Dusting, Jaye P.F., additional, Dominiczak, Anna F., additional, and Jennings, Garry L., additional

Published
2014
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133. Onset of experimental severe cardiac fibrosis is mediated by overexpression of angiotensin-converting enzyme 2

Author

Masson, Rachel, Nicklin, Stuart A., Craig, Margaret Anne, McBride, Martin, Gilday, Kirsten, Gregorevic, Paul, Allen, James M., Chamberlain, Jeffrey S., Smith, Godfrey, Graham, Delyth, Dominiczak, Anna F., Napoli, Claudio, and Baker, Andrew H.

Subjects
QH345, hormones, hormone substitutes, and hormone antagonists, RC
Abstract

Angiotensin-converting enzyme (ACE) 2 is a recently identified homologue of ACE. There is great interest in the therapeutic benefit for ACE2 overexpression in the heart. However, the role of ACE2 in the regulation of cardiac structure and function, as well as maintenance of systemic blood pressure, remains poorly understood. In cell culture, ACE2 overexpression led to markedly increased myocyte volume, assessed in primary rabbit myocytes. To assess ACE2 function in vivo, we used a recombinant adeno-associated virus 6 delivery system to provide 11-week overexpression of ACE2 in the myocardium of stroke-prone spontaneously hypertensive rats. ACE2, as well as the ACE inhibitor enalapril, significantly reduced systolic blood pressure. However, in the heart, ACE2 overexpression resulted in cardiac fibrosis, as assessed by histological analysis with concomitant deficits in ejection fraction and fractional shortening measured by echocardiography. Furthermore, global gene expression profiling demonstrated the activation of profibrotic pathways in the heart mediated by ACE2 gene delivery. This study demonstrates that sustained overexpression of ACE2 in the heart in vivo leads to the onset of severe fibrosis.

Published
2009

141. Validation of Uromodulin as a Candidate Gene for Human Essential Hypertension

Author

Graham, Lesley A., primary, Padmanabhan, Sandosh, additional, Fraser, Niall J., additional, Kumar, Satish, additional, Bates, James M., additional, Raffi, Hajamohideen S., additional, Welsh, Paul, additional, Beattie, Wendy, additional, Hao, Shoujin, additional, Leh, Sabine, additional, Hultstrom, Michael, additional, Ferreri, Nicholas R., additional, Dominiczak, Anna F., additional, Graham, Delyth, additional, and McBride, Martin W., additional

Published
2014
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145. Role of Tumor Necrosis Factor-α and Natural Killer Cells in Uterine Artery Function and Pregnancy Outcome in the Stroke-Prone Spontaneously Hypertensive Rat.

Author

Small, Heather Yvonne, Nosalski, Ryszard, Morgan, Hannah, Beattie, Elisabeth, Guzik, Tomasz J, Graham, Delyth, and Delles, Christian

Abstract

Women with chronic hypertension are at increased risk of maternal and fetal morbidity and mortality. We have previously characterized the stroke-prone spontaneously hypertensive rat (SHRSP) as a model of deficient uterine artery function and adverse pregnancy outcome compared with the control Wistar-Kyoto. The activation of the immune system plays a role in hypertension and adverse pregnancy outcome. Therefore, we investigated the role of tumor necrosis factor-α in the SHRSP phenotype in an intervention study using etanercept (0.8 mg/kg SC) at gestational days 0, 6, 12, and 18 in pregnant SHRSP compared with vehicle-treated controls (n=6). Etanercept treatment significantly lowered systolic blood pressure after gestational day 12 and increased litter size in SHRSP. At gestational day 18, etanercept improved the function of uterine arteries from pregnant SHRSP normalizing the contractile response and increasing endothelium-dependent relaxation, resulting in increased pregnancy-dependent diastolic blood flow in the uterine arteries. We identified that the source of excess tumor necrosis factor-α in the SHRSP was a pregnancy-dependent increase in peripheral and placental CD3- CD161+ natural killer cells. Etanercept treatment also had effects on placental CD161+ cells by reducing the expression of CD161 receptor, which was associated with a decrease in cytotoxic granzyme B expression. Etanercept treatment improves maternal blood pressure, pregnancy outcome, and uterine artery function in SHRSP by antagonizing signaling from excess tumor necrosis factor-α production and the reduction of granzyme B expression in CD161+ natural killer cells in SHRSP. [ABSTRACT FROM AUTHOR]

Published
2016
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