Dr Abdelali Agouni
Lecturer in Cardiovascular Biology
Qualifications: BSc, MSc, PhD
Email: a.agouni@surrey.ac.uk
Phone: Work: 01483 68 2149
Room no: 02 AY 02
Office hours
Normally 9AM-5.30PM
Further information
Biography
2011-present Lecturer in Cardiovascular Biology, University of Surrey, Guildford, UK.
2009-2011 Post-doctoral Research Fellow at the School of Biological Sciences, University of Aberdeen, UK.
2005-2008 PhD in Experimental & Clinical Pharmacology, University of Angers, Angers, France.
2005 MSc in Pharmacology and Pharmaco-chemistry, option Cellular Pharmacology, University Louis Pasteur, Strasbourg, France.
2004 BSc (Maitrise) in Molecular and Cellular Biochemistry, University Louis Pasteur, Strasbourg, France.
2003 BSc in Biochemistry, University Louis Pasteur, Strasbourg, France.
Research Interests
Molecular mechanisms of endothelial dysfunction
Endothelial dysfunction is a hall mark of cardiovascular disease and an early predictor of cardiovascular events; however its molecular origins are not yet fully elucidated. Metabolic situations such as obesity and diabetes are characterized by insulin resistance and inextricably associated with endothelial dysfunction. My research focuses on the identifying the role of new inflammatory and stress pathways in the pathogenesis of endothelial dysfunction.
Role of Tyrosine phosphatases in inflammatory pathways and cardiovascular dysfunction
The main phosphatase of interest to my group is Protein Tyrosine Phosphatase (PTP) 1B. PTP1B is an abundant enzyme with a broad tissue distribution and has long been known to have a major role in inhibiting signalling downstream of the insulin and leptin receptors. PTP1B binds to and dephosphorylates the insulin receptor, thereby inhibiting its tyrosine kinase activity. Similarly, PTP1B targets JAK2 and STAT in the leptin pathway, thereby impeding leptin signals. In collaboration with Dr Mirela Delibegovic (University of Aberdeen), we are investigating the role of PTP1B in obesity-associated cardiovascular dysfunction and in ischemic disease.
Molecular and cellular pathways behind the effects of selenium in health and disease
Selenium is an essential trace nutrient that is believed to exert beneficial effects on human health. Its effects are mainly mediated through its antioxidant capacity. As the amino acid, selenocysteine, selenium is at the active site of antioxidant enzymes such as the glutathione peroxidases and thioredoxin reductases. Selenium has been shown to have many beneficial health effects. For instance, it exerts anti-diabetic and insulin-like properties; however some recent studies have shown that high (supra-nutritional) amounts of selenium are a potential risk factor for developing type-2 diabetes. Type-2 diabetes and its preceding insulin resistance are invariably associated with an increased cardiovascular risk characterized by the impairment of endothelial function commonly referred to endothelial dysfunction, a predictor of future adverse cardiovascular events and an important event in the development of microvascular complications in diabetes. In collaboration Professor Margaret Rayman, we are investigating the cellular and molecular pathways involved both in beneficial and deleterious effects of dietary selenium intake with regards to cardiovascular and diabetes risk.
Microparticles as markers and vectors of cardiovascular disease
Microparticles (MPs) are small membrane vesicles with pro-coagulant properties. MPs are present in blood from healthy individuals and elevated in patients under pathological states, such as sepsis, preeclampsia, Crohn’s disease and also in various clinical situations associated with thrombosis and in diabetic patients, strengthening the notion that MPs may play a role in these diseases. Indeed, MPs can be considered as vectors of biological messages, such as induction of endothelial and vascular dysfunctions or platelet activation. My previous research I highlighted the importance of the stimulus at the origin of MPs shedding in conditioning the message carried out by these MPs. Indeed, MPs generated from the same cell type but by using two different chemical stimuli had opposite effects on endothelial function (deleterious or beneficial). My previous work also focused on the role of circulating MPs in the patho-physiology in different cardiovascular and metabolic situations including metabolic syndrome, sleep apnea and septic shock. I recently initiated new research to further study the involvement of MPs in pathogenesis of heart failure in collaboration with teams in the Heart Institute Sao Paulo (Brazil) and in critically ill patients in collaboration with intensive care unit at the Royal Surrey hospital.
Research Collaborations
Internal Collaborators:
- Prof Margaret Rayman, University of Surrey, Guildford, UK
- Dr Fiona Green, University of Surrey, Guildford, UK
- Dr Rachel Simmonds, University of Surrey, Guildford, UK
- Dr Ben Creagh-Brown, University of Surrey, Royal Surrey County hospital (Intensive Care Unit), Guildford, UK
External Collaborators:
- Dr Mirela Delibegovic, School of Medical Sciences, University of Aberdeen, Scotland, UK
- Dr Nimesh Mody, School of Medical Sciences, University of Aberdeen, Scotland, UK
- Dr Ramaroson Andriantsitohaina, INSERM U694, University of Angers, Angers, France
Publications
Journal articles
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(2012) 'Cellular apoptosis susceptibility (chromosome segregation 1-like, CSE1L) gene is a key regulator of apoptosis, migration and invasion in colorectal cancer'. Wiley Journal of Pathology, 228 (4), pp. 471-481.doi: 10.1002/path.4031
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(2012) 'Serum Levels of Retinol Binding Protein 4 (RBP4) and Adipose Tissue Expression Levels of Protein Tyrosine Phosphatase 1B (PTP1B) are Increased in Obese Men Resident in North East of Scotland Without Any Changes in Endoplasmic Reticulum (ER) Stress Response Marker Genes'. Dove Press International Journal of General Medicine, 2012 (5), pp. 403-411.doi: 10.2147/IJGM.S25879Full text is available at: http://epubs.surrey.ac.uk/401277/
Abstract
Background: Retinol-binding protein 4 (RBP4) is an adipokine identified as a marker of insulin resistance in mice and humans. Protein tyrosine phosphatase 1B (PTP1B) expression levels, as well as other genes involved in the endoplasmic-reticulum (ER) stress response, are increased in adipose tissue of obese, high-fat diet fed mice. In this study, we investigated if serum- and/or adipose-tissue RBP4 protein levels, and expression levels of PTP1B and other ER stress-response genes, are altered in obese and obese/diabetic men resident in North East of Scotland. Methods: We studied three groups of male volunteers: 1) normal/overweight (body mass index (BMI) <30), 2) obese (BMI>30) and 3) obese/diabetic group (BMI>30) controlling their diabetes either by diet or anti-diabetic drug, metformin. We analysed their serum- and adipose-tissue RBP4 protein levels, as well as adipose tissue mRNA expression of PTP1B, BIP (binding immunoglobulinprotein), ATF4 (activated transcription factor 4) and GRP94 (glucose-regulated protein 94), alongside other markers of adiposity (% body fat, leptin, cholesterol, triglycerides) and insulin resistance (oral glucose tolerance tests (OGTT), insulin, HOMA-IR, C-reactive protein (CRP), adiponectin). Results: We found that obese Scottish subjects had significantly higher serum-RBP4 protein levels in comparison to the normal/overweight subjects (p<0.01). Serum-RBP4 levels were normalized in obese/diabetic subjects treated with diet or metformin (p<0.05). Adipose-tissue RBP4 protein levels were comparable between all three groups of subjects and so were serum- and adipose-transthyretin (TTR) levels. Adipose-tissue PTP1B mRNA levels were increased in obese subjects in comparison to normal/overweight subjects (p<0.05), however diet and/or metformin treatment did not reverse this effect. Adipose-tissue BIP, ATF4 and GRP94 expression levels were unchanged in obese and obese/diabetic subjects. Conclusions: Human obesity results in an increase in serum, but not adipose-tissue, RBP4 protein levels and these are normalized in obese/diabetic subjects, which exhibit improvements in insulin sensitivity through diet or metformin treatment. However, whilst adipose-tissue PTP1B mRNA levels do increase in obese Scottish subjects, these remain high in obese/diabetics on diet or metformin treatment.
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(2012) 'Adipocyte-Specific Protein Tyrosine Phosphatase 1B Deletion Increases Lipogenesis,
Adipocyte Cell Size and is a Minor Regulator of Glucose Homeostasis'. PLoS One, 7 (2)Full text is available at: http://epubs.surrey.ac.uk/289614/
Abstract
Protein tyrosine phosphatase 1B (PTP1B), a key negative regulator of leptin and insulin signaling, is positively correlated with adiposity and contributes to insulin resistance. Global PTP1B deletion improves diet-induced obesity and glucose homeostasis via enhanced leptin signaling in the brain and increased insulin signaling in liver and muscle. However, the role of PTP1B in adipocytes is unclear, with studies demonstrating beneficial, detrimental or no effect(s) of adipose-PTP1B-deficiency on body mass and insulin resistance. To definitively establish the role of adipocyte-PTP1B in body mass regulation and glucose homeostasis, adipocyte-specific-PTP1B knockout mice (adip-crePTP1B-/- ) were generated using the adiponectin-promoter to drive Cre-recombinase expression. Chow-fed adip-crePTP1B-/- mice display enlarged adipocytes, despite having similar body weight/adiposity and glucose homeostasis compared to controls. High-fat diet (HFD)-fed adip-crePTP1B-/- mice display no differences in body weight/adiposity but exhibit larger adipocytes, increased circulating glucose and leptin levels, reduced leptin sensitivity and increased basal lipogenesis compared to controls. This is associated with decreased insulin receptor (IR) and Akt/PKB phosphorylation, increased lipogenic gene expression and increased hypoxia-induced factor-1-alpha (Hif-1α) expression. Adipocyte-specific PTP1B deletion does not beneficially manipulate signaling pathways regulating glucose homeostasis, lipid metabolism or adipokine secretion in adipocytes. Moreover, PTP1B does not appear to be the major negative regulator of the IR in adipocytes.
- . (2012) 'Correction: Adipocyte-Specific Protein Tyrosine Phosphatase 1B Deletion Increases Lipogenesis, Adipocyte Cell Size and Is a Minor Regulator of Glucose Homeostasis.'. PLoS One, 7 (5)
- . (2011) 'Protection by Red Wine Polyphenols against Metabolic and Cardiovascular Alterations Associated with Obesity: A Possible Link with Estrogen Alpha Receptor'. Journal of Wine Research, 22 (2), pp. 151-157.
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(2011) 'Microparticles from apoptotic monocytes enhance nitrosative stress in human endothelial cells.'. Wiley Fundam Clin Pharmacol, England: 25 (6), pp. 653-660.Full text is available at: http://epubs.surrey.ac.uk/158047/
Abstract
Microparticles are membrane vesicles with procoagulant and proinflammatory properties released during cell activation or apoptosis. Microparticles from monocytes have been implicated in atherosclerosis and vascular inflammation, but their direct effects on endothelial cells are not completely elucidated. The present study was designed to dissect the signaling pathways of monocytic microparticles in endothelial cells with respect to both NO pathway and reactive oxygen species. Microparticles were produced by treatment of human monocytic cell line THP-1 with the apoptotic agent VP-16. Human endothelial cells were treated with monocytic microparticles and then, we studied their effects on nitrosative and oxidative stresses. Incubation of human endothelial cells with microparticles enhanced the production of NO without affecting superoxide anions generation. Microparticles did not affect endothelial NO synthase expression and its phosphorylation. Interestingly, microparticles decreased caveolin-1 expression and increased its phosphorylation. Inhibition of PI-3-kinase or MEK1/2 reversed the effects of microparticles on caveolin-1 expression but not its phosphorylation. Moreover, microparticles increased nitration of several proteins, reflecting peroxynitrite production, which was prevented by blockade of PI-3-kinase pathway. In summary, monocyte microparticles active multiple pathways related to nitrosative stress in endothelial cells including both PI-3-kinase and ERK1/2 in the regulation of caveolin-1 expression. These data underscore the pleiotropic effect of microparticles on endothelial cells and suggest that they probably play a critical role on vascular function.
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(2011) 'Microparticles from patients with metabolic syndrome induce vascular hypo-reactivity
via Fas/Fas-Ligand pathway in mice'. PLoS PloS ONE, 6 (11) Article number e27809 Full text is available at: http://epubs.surrey.ac.uk/158088/
Abstract
Microparticles are membrane vesicles with pro-inflammatory properties. Circulating levels of microparticles have previously been found to be elevated in patients with metabolic syndrome (MetS). The present study aimed to evaluate the effects of in vivo treatment with microparticles, from patients with MetS and from healthy subjects (HS), on ex vivo vascular function in mice. Microparticles isolated from MetS patients or HS, or a vehicle were intravenously injected into mice, following which vascular reactivity in response to vasoconstrictor agonists was assessed by myography with respect to cyclo-oxygenase pathway, oxidative and nitrosative stress. Injection of microparticles from MetS patients into mice induced vascular hyporeactivity in response to serotonin. Hypo-reactivity was associated with up-regulation of inducible NO-synthase and increased production of NO, and was reversed by the NOsynthase inhibitor (NG-nitro-L-arginine). The selective COX-2 inhibitor (NS398) reduced the contractile effect of serotonin in aortas from mice treated with vehicle or HS microparticles; however, this was not observed within mice treated with MetS microparticles, probably due to the ability of MetS microparticles to enhance prostacyclin. MetS microparticle-mediated vascular dysfunction was associated with increased reactive oxygen species (ROS) and enhanced expression of the NADPH oxidase subunits. Neutralization of the pro-inflammatory pathway Fas/FasL completely prevented vascular hypo-reactivity and the ability of MetS microparticles to enhance both inducible NO-synthase and monocyte chemoattractant protein-1 (MCP-1). Our data provide evidence that microparticles from MetS patients induce ex vivo vascular dysfunction by increasing both ROS and NO release and by altering cyclooxygenase metabolites and MCP-1 through the Fas/FasL pathway.
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(2011) 'Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress'. PORTLAND PRESS LTD BIOCHEMICAL JOURNAL, 438, pp. 369-378.doi: 10.1042/BJ20110373Full text is available at: http://epubs.surrey.ac.uk/158030/
- . (2011) 'Susceptibility to diet-induced obesity and glucose intolerance in the APP (SWE)/PSEN1 (A246E) mouse model of Alzheimer's disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein'. SPRINGER DIABETOLOGIA, 54 (8), pp. 2143-2151.
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(2011) 'Role of G(i/o)-Src kinase-PI3K/Akt pathway and caveolin-1 in beta(2)-adrenoceptor coupling to endothelial NO synthase in mouse pulmonary artery'. ELSEVIER SCIENCE INC CELLULAR SIGNALLING, 23 (7), pp. 1136-1143.Full text is available at: http://epubs.surrey.ac.uk/158171/
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(2010) 'In vivo differential effects of fasting, re-feeding, insulin and insulin stimulation time course on insulin signaling pathway components in peripheral tissues.'. Elsevier Biochem Biophys Res Commun, United States: 401 (1), pp. 104-111.Full text is available at: http://epubs.surrey.ac.uk/157950/
Abstract
Components of the insulin receptor signaling pathway are probably some of the best studied ones. Even though methods for studying these components are well established, the in vivo effects of different fasting regimens, and the time course of insulin receptor phosphorylation and that of its downstream components in insulin-sensitive peripheral tissues have not been analyzed in detail.
- . (2010) 'Endothelial dysfunction and circulating microparticles from patients with obstructive sleep apnea.'. Am J Pathol, United States: 177 (2), pp. 974-983.
- . (2010) 'Liver-specific Deletion of Protein Tyrosine Phosphatase (PTP) 1B Improves Endothelial Dysfunction and Cardiovascular Alterations Associated with Obesity in mice'. FEDERATION AMER SOC EXP BIOL FASEB JOURNAL, 24
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(2009) 'Red wine polyphenols prevent metabolic and cardiovascular alterations associated with obesity in Zucker fatty rats (Fa/Fa).'. PLoS PLoS One, United States: 4 (5)Full text is available at: http://epubs.surrey.ac.uk/158132/
Abstract
Obesity is associated with increased risks for development of cardiovascular diseases. Epidemiological studies report an inverse association between dietary flavonoid consumption and mortality from cardiovascular diseases. We studied the potential beneficial effects of dietary supplementation of red wine polyphenol extract, Provinols, on obesity-associated alterations with respect to metabolic disturbances and cardiovascular functions in Zucker fatty (ZF) rats.
- . (2008) 'Circulating microparticles from patients with septic shock exert protective role in vascular function.'. Am J Respir Crit Care Med, United States: 178 (11), pp. 1148-1155.
- . (2008) 'Endothelial dysfunction caused by circulating microparticles from patients with metabolic syndrome.'. Am J Pathol, United States: 173 (4), pp. 1210-1219.
- . (2008) 'Phosphatidylinositol 3-kinase and xanthine oxidase regulate nitric oxide and reactive oxygen species productions by apoptotic lymphocyte microparticles in endothelial cells.'. J Immunol, United States: 180 (7), pp. 5028-5035.
- . (2007) 'Sonic hedgehog carried by microparticles corrects endothelial injury through nitric oxide release.'. FASEB J, United States: 21 (11), pp. 2735-2741.
- . (2007) 'Parathyroid hormone-related protein induces cell survival in human renal cell carcinoma through the PI3K Akt pathway: evidence for a critical role for integrin-linked kinase and nuclear factor kappa B.'. Carcinogenesis, England: 28 (9), pp. 1893-1901.
- . (2006) 'The phosphoinositide 3-kinase/Akt pathway: a new target in human renal cell carcinoma therapy.'. Cancer Res, United States: 66 (10), pp. 5130-5142.
Conference papers
- . (2012) 'Liver-specific Deletion of Protein Tyrosine Phosphatase (PTP) 1B Improves Endothelial Dysfunction and Cardiovascular Alterations Associated with Obesity in mice'. FEDERATION AMER SOC EXP BIOL FASEB JOURNAL, San Diego, CA: Experimental Biology Meeting 26
- . (2010) 'Protein Tyrosine Phosphatase 1B Is Involved in Endoplasmic Reticulum Stress Response in Both Hepatocytes and Adipocytes'. AMER DIABETES ASSOC DIABETES, Orlando, FL: 70th Annual Meeting of the American-Diabetes-Association 59, pp. A385-A385.
- . (2008) 'Microparticles from patients with metabolic syndrome induce in vivo vascular hypo-reactivity via Fas/Fas-Ligand pathway by increasing oxidative and nitrosative stresses in mouse aorta'. LIPPINCOTT WILLIAMS & WILKINS HYPERTENSION, Nice, FRANCE: 13th Annual Meeting of the European-Council-for-Cardiovascular-Research 52 (4), pp. 758-758.
- . (2008) 'Microparticles from patients with metabolic syndrome induce in vivo endothelial dysfunction and vascular hypo-reactivity by increasing oxidative and nitrosative stresses in mouse aorta'. BLACKWELL PUBLISHING FUND CLIN PHARMACOL, 22, pp. 31-31.
- . (2008) 'Paradoxical effect of red wine polyphenols, Provinols (TM) fit the regulation of cyclo-oxygenases in vessels front Zucker fatty rats (Fa/Fa)'. BLACKWELL PUBLISHING FUNDAMENTAL & CLINICAL PHARMACOLOGY, 22, pp. 95-95.
- . (2008) 'Role of caveolae and eNOS phosphorylation in the beta 2-adrenoceptor-mediated relaxation in mice pulmonary arteries'. ACADEMIC PRESS INC ELSEVIER SCIENCE NITRIC OXIDE-BIOLOGY AND CHEMISTRY, Bregenz, AUSTRIA: 5th International Conference on Biology, Chemistry, and Therapeutic Applications of Nitric Oxide 19, pp. S69-S70.
- . (2007) 'Sonic Hedgehog carried by microparticles corrects endothelial injury through nitric oxide release'. LIPPINCOTT WILLIAMS & WILKINS CIRCULATION, Orlando, FL: 80th Annual Scientific Session of the American-Heart-Association 116 (16), pp. 74-74.
- . (2007) 'Sonic hedgehog carried by microparticles corrects endothelial injury and promotes angiogenesis through nitric oxide release'. BLACKWELL PUBLISHING FUNDAMENTAL & CLINICAL PHARMACOLOGY, 21, pp. 21-21.
- . (2007) 'Red wine polyphenols, Provinols (TM), improve endothelial function via an increase of nitric oxide production and a reduced oxidative stress in Zucker fatty rats Fa/Fa'. BLACKWELL PUBLISHING FUNDAMENTAL & CLINICAL PHARMACOLOGY, 21, pp. 6-6.
- . (2007) 'Cross-link between PI3-kinase and MAP kinase pathways in the regulation of NO signaling and increase in reactive oxygen species production by apoptotic T lymphocyte microparticles in endothelial cells'. BLACKWELL PUBLISHING FUNDAMENTAL & CLINICAL PHARMACOLOGY, 21, pp. 19-20.
- . (2007) 'Circulating microparticles from septic chock patients exert protective role on vascular function'. BLACKWELL PUBLISHING FUND CLIN PHARMACOL, 21, pp. 24-24.
- . (2007) 'Parathyroid hormone-related protein induces cell survival in human renal cell carcinoma through the PI3K/AKT pathway: Evidence for a critical role for integrin-linked kinase and nuclear factor kappa B'. ELSEVIER SCIENCE INC JOURNAL OF UROLOGY, Anaheim, CA: 102nd Annual Meeting of the American-Urological-Association 177 (4), pp. 149-149.
Affiliations
- Member Groupe de Reflexion sur la Recherche Cardiovasculaire (GRRC) (France).
- Member Societe de Physiologie (France).
- Ordinary member of the Physiological Society (UK).
- Member of the Biochemical Society (UK).
Fundraising and Research Grants
Grants and Awards:
- Research Grant, The Royal Society 2013-2014 ~£15,000
- Faculty Research Support Fund, University of Surrey 2012-2013 ~£16,000
- Research Grant, The Physiological Society, 2012-2013 ~£10,000
- Research Grant, Tenovus Scotland, 2011-2012 ~£10,000
- Banco Santander student mobility scholarship 2012 £5,000
- University Global Network Partnership (UGPN) fund 2012 £5,000
- Several travelling fellowships and grants (a total of ~£5,000)
