Imperial College London

ProfessorJaneMitchell

Faculty of MedicineNational Heart & Lung Institute

Professor of Pharmacology in Critical Care Medicine
 
 
 
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Contact

 

+44 (0)20 7351 8137j.a.mitchell

 
 
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Location

 

Guy Scadding BuildingRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
to

404 results found

Ahmetaj-Shala B, Marei I, Kawai R, Rothery S, Pericleous C, Mohamed N, Gashaw H, Bokea K, Samuel J, Vandenheste A, Shala F, Kirkby N, Mitchell Jet al., 2021, Activation and contraction of human ‘vascular’ smooth muscle cells grown from circulating blood progenitors, Frontiers in Cell and Developmental Biology, ISSN: 2296-634X

Blood outgrowth smooth muscle cells offer the means to study vascular cells without the requirement for surgery providing opportunities for drug discovery, tissue engineering and personalised medicine. However, little is known about these cells which has meant their therapeutic potential remains unexplored. Our objective was to investigate for the first time the ability of blood outgrowth smooth muscle cells and vessel derived smooth muscle cells to sense the thromboxane mimetic U46619 bymeasuring intracellular calcium elevation and contraction. U46619 (10 26 -6M) increased cytosolic calcium in blood outgrowth smooth muscle cells fibroblasts. Increased calcium signal peaked between 10-20 seconds after U46619 in both smoothmuscle cell types. Importantly, U46619 (10-9 to 10-6M) induced concentration-dependent contractions of both blood outgrowth smooth muscle cells and vascular smooth muscle cells but not in fibroblasts. In summary, we show that functional responses of blood outgrowth smooth muscle cells are in line with vascular smooth muscle cells providing critical evidence of their application in biomedical research.

Journal article

Mitchell J, Shala F, Lopes Pires M, Loy R, Ravendren A, Benson J, Urquhart P, Nicolaou A, Herschman H, Kirkby Net al., 2021, Endothelial cyclooxygenase-1 paradoxically drives local vasoconstriction and atherogenesis despite underpinning prostacyclin generation, Science Advances, Vol: 7, ISSN: 2375-2548

Endothelial cyclooxygenase-1–derived prostanoids, including prostacyclin, have clear cardioprotective roles associated with their anti-thrombotic potential but have also been suggested to have paradoxical pathological activities within arteries. To date it has not been possible to test the importance of this because no models have been available that separate vascular cyclooxygenase-1 products from those generated elsewhere. Here, we have used unique endothelial-specific cyclooxygenase-1 knockout mice to show that endothelial cyclooxygenase-1 produces both protective and pathological products. Functionally, however, the overall effect of these was to drive pathological responses in the context of both vasoconstriction in vitro and the development of atherosclerosis and vascular inflammation in vivo. These data provide the first demonstration of a pathological role for the vascular cyclooxygenase-1 pathway, highlighting its potential as a therapeutic target. They also emphasize that, across biology, the role of prostanoids is not always predictable due to unique balances of context, products, and receptors.

Journal article

Mohamed NA, Abou-Saleh H, Kameno Y, Marei I, de Nucci G, Ahmetaj-Shala B, Shala F, Kirkby NS, Jennings L, Al-Ansari DE, Davies RP, Lickiss PD, Mitchell JAet al., 2021, Studies on metal-organic framework (MOF) nanomedicine preparations of sildenafil for the future treatment of pulmonary arterial hypertension, Scientific Reports, Vol: 11, Pages: 1-8, ISSN: 2045-2322

Pulmonary arterial hypertension (PAH) is an incurable disease, although symptoms are treated with a range of dilator drugs. Despite their clinical benefits, these drugs are limited by systemic side-effects. It is, therefore, increasingly recognised that using controlled drug-release nanoformulation, with future modifications for targeted drug delivery, may overcome these limitations. This study presents the first evaluation of a promising nanoformulation (highly porous iron-based metal–organic framework (MOF); nanoMIL-89) as a carrier for the PAH-drug sildenafil, which we have previously shown to be relatively non-toxic in vitro and well-tolerated in vivo. In this study, nanoMIL-89 was prepared and charged with a payload of sildenafil (generating Sil@nanoMIL-89). Sildenafil release was measured by Enzyme-Linked Immunosorbent Assay (ELISA), and its effect on cell viability and dilator function in mouse aorta were assessed. Results showed that Sil@nanoMIL-89 released sildenafil over 6 h, followed by a more sustained release over 72 h. Sil@nanoMIL-89 showed no significant toxicity in human blood outgrowth endothelial cells for concentrations up to100µg/ml; however, it reduced the viability of the human pulmonary artery smooth muscle cells (HPASMCs) at concentrations > 3 µg/ml without inducing cellular cytotoxicity. Finally, Sil@nanoMIL-89 induced vasodilation of mouse aorta after a lag phase of 2–4 h. To our knowledge, this study represents the first demonstration of a novel nanoformulation displaying delayed drug release corresponding to vasodilator activity. Further pharmacological assessment of our nanoformulation, including in PAH models, is required and constitutes the subject of ongoing investigations.

Journal article

Mitchell JA, Kirkby NS, Ahmetaj-Shala B, Armstrong P, Crescente M, Ferreira P, Pires MEL, Vaja RK, Warner TDet al., 2021, Cyclooxygenases and the cardiovascular system, Pharmacology and Therapeutics, Vol: 217, Pages: 1-11, ISSN: 0163-7258

Cyclooxygenase (COX)-1 and COX-2 are centrally important enzymes within the cardiovascular system with a range of diverse, sometimes opposing, functions. Through the production of thromboxane, COX in platelets is a pro-thrombotic enzyme. By contrast, through the production of prostacyclin, COX in endothelial cells is antithrombotic and in the kidney regulates renal function and blood pressure. Drug inhibition of COX within the cardiovascular system is important for both therapeutic intervention with low dose aspirin and for the manifestation of side effects caused by nonsteroidal anti-inflammatory drugs. This review focuses on the role that COX enzymes and drugs that act on COX pathways have within the cardiovascular system and provides an in-depth resource covering COX biology and pharmacology. The review goes on to consider the role of COX in both discrete cardiovascular locations and in associated organs that contribute to cardiovascular health. We discuss the importance of, and strategies to manipulate, the thromboxane: prostacyclin balance. Finally within this review the authors discuss testable COX-2-hypotheses intended to stimulate debate and facilitate future research and therapeutic opportunities within the field.

Journal article

Ahmetaj-Shala B, Ricky V, Santosh A, Peter G, Nicholas K, Jane Met al., 2020, Cardiorenal tissues express SARS-CoV-2 entry genes and basigin (BSG/CD147) increases with age in endothelial cells, JACC: Basic to Translational Science, Vol: 5, Pages: 1111-1123, ISSN: 2452-302X

Objectives: To obtain mechanistic insight into COVID-19 within a cardiovascular setting.Background: Thrombosis and vascular dysfunction are part of the complex pathology seen in severe COVID-19 and advancing age is the most significant risk factor. Little is known about age and expression of pathways utilised by the COVID-19 virus, SARS-CoV-2, in cardiovascular tissues.Methods: We used publicly available databases (GTEx, GEO and Array Express) to investigate gene expression levels, in adult tissues, of the two putative SARS-CoV-2 receptors, ACE2 and BSG along with a selected range of genes thought to be involved in virus binding/processing. Our analysis included; vessels (aorta and coronary artery), heart (atrial appendage and left ventricle), kidney (cortex), whole blood, lung, colon and spleen along with endothelial cells, nasal and bronchial epithelium and peripheral blood mononuclear cells. Gene expression levels were then analysed for age associations.Results: We found: (i) cardiovascular tissues/endothelial cells express the required genes for SARS-CoV-2 infection, (ii) SARS-CoV-2 receptor pathways, ACE2/TMPRSS2 and BSG/PPIB(A) polarise to lung/epithelium and vessel/endothelium respectively, (iii) expression of host genes are relatively stable with age and (iv) notable exceptions are ACE2 which decreases with age in some tissues and BSG which increases with age in endothelial cells.Conclusion: Our data identifies a positive correlation of BSG with age in endothelial cells. Since BSG is utilised by other pathogens and is implicated in a range of cardiovascular disease, our observations may have relevance to our understanding of mechanisms associated with other pathogens and in the diseases associated with aging respectively.

Journal article

Kirkby N, Raouf J, Ahmetaj-Shala B, Liu B, Mazi S, Edin M, Geoffrey Chambers M, Korotkova M, Wang X, Wahli W, Zeldin D, Nusing R, Zhou Y, Jakobsson P-J, Mitchell Jet al., 2020, Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis, Cardiovascular Research, Vol: 116, Pages: 1972-1980, ISSN: 0008-6363

Aims:Cardiovascular side effects caused by non-steroidal anti-inflammatory drugs (NSAIDs), which all inhibit cyclooxygenase (COX)-2, have prevented development of new drugs that target prostaglandins to treat inflammation and cancer. Microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors have efficacy in the NSAID arena but their cardiovascular safety is not known. Our previous work identified asymmetric dimethylarginine (ADMA), an inhibitor of eNOS, as a potential biomarker of cardiovascular toxicity associated with blockade of COX-2. Here we have used pharmacological tools and genetically modified mice to delineate mPGES-1 and COX-2 in the regulation of ADMA.Methods and Results:Inhibition of COX-2 but not mPGES-1 deletion resulted in increased plasma ADMA levels. mPGES-1 deletion but not COX-2 inhibition resulted in increased plasma prostacyclin levels. These differences were explained by distinct compartmentalisation of COX-2 and mPGES-1 in the kidney. Data from prostanoid synthase/receptor knockout mice showed that the COX-2/ADMA axis is controlled by prostacyclin receptors (IP and PPARβ/δ) and the inhibitory PGE2 receptor EP4, but not other PGE2 receptors.Conclusions:These data demonstrate that inhibition of mPGES-1 spares the renal COX-2/ADMA pathway and define mechanistically how COX-2 regulates ADMA.

Journal article

Vaja R, Chan J, Ferreira P, Harky A, Rogers LJ, Gashaw HH, Kirkby NS, Mitchell JAet al., 2020, The COVID-19 ibuprofen controversy: A systematic review of NSAIDs in adult acute lower respiratory tract infections, BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Vol: 87, Pages: 776-784, ISSN: 0306-5251

Journal article

Crescente M, Armstrong P, Kirkby N, Edin M, Chan M, Lih F, Maffucci T, Allan H, Mein C, Gaston-Massuet C, Cottrell G, Zeldin D, Herschman H, Warner Tet al., 2020, Profiling the eicosanoid networks that underlie the anti- and pro-thrombotic effects of aspirin, The FASEB Journal, ISSN: 0892-6638

Aspirin preventsthrombosisby inhibiting platelet cyclooxygenase (COX)-1 activity and the production of thromboxane (Tx)A2, a pro-thrombotic eicosanoid. However, thenon-platelet actions ofaspirin limit its anti-thrombotic effects. Here we used platelet-COX-1-komice to define the platelet andnon-platelet eicosanoids affected by aspirin.Mass-spectrometry analysis demonstrated blood fromplatelet-COX-1-ko and global-COX-1-ko mice produced similar eicosanoid profiles in vitro: e.g. formation of TxA2,prostaglandin (PG) F2a, 11-HETE and 15-HETE was absent in both platelet-and global-COX-1-komice. Conversely, in vivo,platelet-COX-1-ko mice had a distinctly different profile from global-COX-1-koor aspirin-treated controlmice, notably significantly higher levels of PGI2metabolite. Ingenuity Pathway Analysis predicted that platelet-COX-1-ko mice would be protected from thrombosis,formingless prothrombotic TxA2 and PGE2. Conversely, aspirinor lack of systemic COX-1 activity decreased the synthesis of anti-aggregatory PGI2and PGD2 at non-platelet sites leading to predictedthrombosis increase. In vitroand in vivothrombosis studies proved these predictions. Overall, we have established the eicosanoid profileslinked to inhibition of COX-1 in platelets and in the remainder of the cardiovascular systemand linked them to anti-and pro-thrombotic effects of aspirin. These results explainwhy increasing aspirin dosage or aspirin addition to other drugs may lessenanti-thrombotic protection.

Journal article

Ahmetaj-Shala B, Kawai R, Marei I, Nikolakopoulou Z, Shih C-C, Konain B, Reed DM, Mongey R, Kirkby NS, Mitchell JAet al., 2020, A bioassay system of autologous human endothelial, smooth muscle cells and leucocytes for use in drug discovery, phenotyping and tissue engineering, The FASEB Journal, Vol: 34, Pages: 1745-1754, ISSN: 0892-6638

Purpose: Blood vessels are comprised of endothelial and smooth muscle cells. Obtaining both types of cells from vessels of living donors is not possible without invasive surgery. To address this we have devised a strategy whereby human endothelial and smooth muscle cells derived from blood progenitors from the same donor could be cultured with autologous leucocytes to generate a same donor ‘vessel in a dish’ bioassay. Basic procedures: Autologous sets of blood outgrowth endothelial cells (BOECs), smooth muscle cells (BO-SMCs) and leucocytes were obtained from 4 donors. Cells were treated in mono and cumulative co-culture conditions. The endothelial specific mediator endothelin-1 along with interleukin (IL)-6, IL-8, tumour necrosis factor α, and interferon gamma-induced protein 10 were measured under control culture conditions and after stimulation with cytokines.Main findings: Co-cultures remained viable throughout. The profile of individual mediators released from cells was consistent with what we know of endothelial and smooth muscle cells cultured from blood vessels.Principle conclusions: For the first time, we report a proof of concept study where autologous blood outgrowth ‘vascular’ cells and leucocytes were studied alone and in co-culture. This novel bioassay has utility in vascular biology research, patient phenotyping, drug testing and tissue engineering.

Journal article

Mitchell J, Shala F, Elghazouli Y, Warner T, Gaston-Massuet C, Crescente M, Armstrong P, Herschman H, Kirkby Net al., 2019, Cell-Specific Gene Deletion Reveals the Antithrombotic Function of COX1 and Explains the Vascular COX1/Prostacyclin Paradox, Circulation Research, Vol: 125, Pages: 847-854, ISSN: 0009-7330

Rationale: Endothelial cells and platelets, which respectively produce anti-thrombotic prostacyclin and pro-thrombotic thromboxane A2, both express COX1. Consequently, there has been no way to delineate any anti-thrombotic role for COX1-derived prostacyclin from the pro-thrombotic effects of platelet COX1. By contrast an anti-thrombotic role for COX2, which is absent in platelets, is straightforward to demonstrate. This has resulted in an incomplete understanding of the relative importance of COX1 versus COX2 in prostacyclin production and anti-thrombotic protection in vivo.Objective: We sought to identify the role, if any, of COX1-derived prostacyclin in anti-thrombotic protection in vivo and compare this to the established protective role of COX2.Methods and Results: We developed vascular-specific COX1 knockout mice and studied them alongside endothelial-specific COX2 knockout mice. COX1 immunoreactivity and prostacyclin production were primarily associated with the endothelial layer of aortae; freshly isolated aortic endothelial cells released >10-fold more prostacyclin than smooth muscle cells. Moreover, aortic prostacyclin production, the ability of aortic rings to inhibit platelet aggregation and plasma prostacyclin levels were reduced when COX1 was knocked out in endothelial cells but not in smooth muscle cells. When thrombosis was measured in vivo after FeCl3 carotid artery injury, endothelial COX1 deletion accelerated thrombosis to a similar extent as prostacyclin receptor blockade. However, but this effect was lost when COX1 was deleted from both endothelial cells and platelets. Deletion of COX2 from endothelial cells also resulted in a pro-thrombotic phenotype that was independent of local vascular prostacyclin production.Conclusions:These data demonstrate for the first time that, in healthy animals, endothelial COX1 provides an essential anti-thrombotic tone, which is masked when COX1 activity is lost in both endothelial cells and platelets. These res

Journal article

George PM, Mitchell JA, 2019, Defining a pathological role for the vasculature in the development of fibrosis and pulmonary hypertension in interstitial lung disease, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 317, Pages: L431-L433, ISSN: 1040-0605

Journal article

Marei I, Mongey R, Gashaw H, Mitchell JAet al., 2019, Isolation of blood outgrowth endothelial cells under shear conditions: A move towards a more physiological vascular cell platform, British-Pharmacology-Society Meeting (Pharmacology), Publisher: WILEY, Pages: 3033-3033, ISSN: 0007-1188

Conference paper

Ahmetaj-Shala B, Kawai R, Marei I, Bhatti F, Gashaw H, Kirkby NS, Mitchell JAet al., 2019, A bioassay system of autologous human endothelial and smooth muscle cells for use in cardiovascular drug discovery and patient phenotyping, British-Pharmacology-Society Meeting (Pharmacology), Publisher: WILEY, Pages: 3040-3041, ISSN: 0007-1188

Conference paper

Mohamed NA, Davies RP, Lickiss PD, Kameno Y, Marei I, Kirkby NS, Mitchell JA, Abou Saleh Het al., 2019, Mil-89 nanoformulation as a platform to improve pulmonary arterial hypertension treatment, British-Pharmacology-Society Meeting (Pharmacology), Publisher: WILEY, Pages: 3075-3075, ISSN: 0007-1188

Conference paper

Marei I, Al Shammari H, Latif N, Ahmetaj-Shala B, Yacoub MH, Chester AH, Mitchell JAet al., 2019, Effect of toll-like receptor antagonists on side specific aortic valve endothelial cells, British-Pharmacology-Society Meeting (Pharmacology), Publisher: WILEY, Pages: 2999-3000, ISSN: 0007-1188

Conference paper

Mazi SI, Ahmetaj-Shala B, Warner TD, Mitchell JA, Kirkby NSet al., 2019, Omic profiling in healthy volunteers taking celecoxib reveals novel biomarkers regulated by cyclooxygenase-2, British-Pharmacology-Society Meeting (Pharmacology), Publisher: WILEY, Pages: 1628-1628, ISSN: 0306-5251

Conference paper

Ciano M, Mantellato G, Connolly M, Paul-Clark M, Mitchell J, Wilson-Owen S, Cookson W, Moffatt M, Hughes S, Polkey M, Kemp P, Natanek Set al., 2019, EGF receptor (EGFR) inhibition promotes a slow-twitch oxidative, over a fast-twitch, muscle phenotype, Scientific Reports, Vol: 9, ISSN: 2045-2322

A low quadriceps slow-twitch (ST), oxidative (relative to fast-twitch) fiber proportion is prevalent in chronic diseases such Chronic Obstructive Pulmonary Disease (COPD) and is associated with exercise limitation and poor outcomes. Benefits of an increased ST fiber proportion are demonstrated in genetically modified animals. Pathway analysis of published data of differentially expressed genes in mouse ST and FT fibers, mining of our microarray data and a qPCR analysis of quadriceps specimens from COPD patients and controls were performed. ST markers were quantified in C2C12 myotubes with EGF-neutralizing antibody, EGFR inhibitor or an EGFR-silencing RNA added. A zebrafish egfra mutant was generated by genome editing and ST fibers counted. EGF signaling was (negatively) associated with the ST muscle phenotype in mice and humans, and muscle EGF transcript levels were raised in COPD. In C2C12 myotubes, EGFR inhibition/silencing increased ST, including mitochondrial, markers. In zebrafish, egfra depletion increased ST fibers and mitochondrial content. EGF is negatively associated with ST muscle phenotype in mice, healthy humans and COPD patients. EGFR blockade promotes the ST phenotype in myotubes and zebrafish embryos. EGF signaling suppresses the ST phenotype, therefore EGFR inhibitors may be potential treatments for COPD-related muscle ST fiber loss.

Journal article

Lucotti S, Cerutti C, Soyer M, Gil-Bernabe AM, Gomes AL, Allen PD, Smart S, Markelc B, Watson K, Armstrong PC, Mitchell JA, Warner TD, Ridley AJ, Muschel RJet al., 2019, Aspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A(2), JOURNAL OF CLINICAL INVESTIGATION, Vol: 129, Pages: 1845-1862, ISSN: 0021-9738

Journal article

Akhmedov D, Kirkby NS, Mitchell JA, Berdeaux Ret al., 2019, Imaging of Tissue-Specific and Temporal Activation of GPCR Signaling Using DREADD Knock-In Mice., Pages: 361-376

Engineered G protein-coupled receptors (DREADDs, designer receptors exclusively activated by designer drugs) are convenient tools for specific activation of GPCR signaling in many cell types. DREADDs have been utilized as research tools to study numerous cellular and physiologic processes, including regulation of neuronal activity, behavior, and metabolism. Mice with random insertion transgenes and adeno-associated viruses have been widely used to express DREADDs in individual cell types. We recently created and characterized ROSA26-GsDREADD knock-in mice to allow Cre recombinase-dependent expression of a Gαs-coupled DREADD (GsD) fused to GFP in distinct cell populations in vivo. These animals also harbor a CREB-activated luciferase reporter gene for analysis of CREB activity by in vivo imaging, ex vivo imaging, or biochemical reporter assays. In this chapter, we provide detailed methods for breeding GsD animals, inducing GsD expression, stimulating GsD activity, and measuring basal and stimulated CREB reporter bioluminescence in tissues in vivo, ex vivo, and in vitro. These animals are available from our laboratory for non-profit research.

Book chapter

Mitchell J, Kirkby NS, 2019, Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system, British Journal of Pharmacology, Vol: 176, Pages: 1038-1050, ISSN: 1476-5381

Eicosanoids represent a diverse family of lipid mediators with fundamental roles in controlling physiology and disease. Within the eicosanoid super family are prostanoids, which are specifically derived from arachidonic acid by the enzyme cyclooxygenase(COX). COX has two isoforms; COX-1 and COX-2. COX-2 is the therapeutic target for the nonsteroidal anti-inflammatory drug (NSAID) class of pain medications. Of the prostanoids,prostacyclin, first discovered by Sir Professor John Vane in 1976,remains amongst the best studied and retains an impressive pedigree as onethe bodies fundamental cardiovascular protective pathways. Since this time, we have learnt much about how eicosanoids, COXenzymes and prostacyclin function in the cardiovascular system which has allowed us to, for example, harness the power of prostacyclin as therapy to treat pulmonary arterial hypertension and peripheral vascular disease. However, there remain many unanswered questions in our basic understanding of the pathways and how they can be usedto improve human health. Perhaps the most importantand controversial outstanding question in the field remains;‘how do NSAIDsproduce their much publicized cardiovascular side effects?’This review summarises the history, biology and cardiovascular function of key eicosanoids with particular focus on prostacyclin and other COXproducts and discusses how our knowledge of these pathways can applied in future drug discovery and be used to explain the cardiovascular side effects of NSAIDs.

Journal article

Alvarez-Fuente M, Moreno L, Mitchell JA, Reiss IK, Lopez P, Elorza D, Duijts L, Avila-Alvarez A, Arruza L, Ramirez Orellana M, Baraldi E, Zaramella P, Rueda S, Gimeno-Diaz de Atauri A, Guimaraes H, Rocha G, Proenca E, Thebaud B, Jesus del Cerro Met al., 2019, Preventing bronchopulmonary dysplasia: new tools for an old challenge, PEDIATRIC RESEARCH, Vol: 85, Pages: 432-441, ISSN: 0031-3998

Journal article

Mitchell JA, Bishop-Bailey D, 2019, PPARβ/δ a potential target in pulmonary hypertension blighted by cancer risk, Pulmonary Circulation, Vol: 9, Pages: 1-2, ISSN: 2045-8940

Journal article

Mitchell J, Bishop-Bailey D, 2018, PPARβ/δ a potential target in pulmonary hypertension blighted by cancer risk., Pulmonary Circulation, ISSN: 2045-8940

Dear Editor,Our group and others have used preclinical in vitro and in vivo models that highlight the potential therapeutic benefit of PPARβ/δ as a target in the treatment of pulmonary arterial hypertension. Selective agonists of PPARβ/δ inhibit fibroblast and pulmonary arterial vascular smooth muscle cell growth and prevent right heart hypertrophy in rat models of pulmonary arterial hypertension. Further work published in Pulmonary Circulation established the transcriptomic profile and pathways associated with activating PPARβ/δ in a model of pulmonary artery banding and right heart hypertrophy (1). These results and the fact that enhancing PPARβ/δ is linked to increased endurance exercise performance (2) supports the idea that drugs working on this pathway could be beneficial in pulmonary arterial hypertension. However, there is cause for concern regarding at least one drug that activates PPARβ/δ, GW501516, developed by GlaxoSmithKline plc (GSK) in the early 2000’s. Despite these concerns and although not confirmed in humans, following the publication of endurance exercise studies in rodents, a significant underground market has developed for unlicensed GW501516 (also referred to as Endurobol or Cardarine) in a bid to enhance human athletic performance. PPARβ/δ agonists, including GW501516 were developed for the treatment of hyperlipidemia and other cardiovascular diseases and a number of clinical trails have been registered on clinicaltrials.gov (Clinical trials id NCT00388180; NCT00318617; NCT00158899; NCT00841217). Whilst, long term clinical data are not available, GW501516 improved lipid profiles in short term studies in man (3-5). However safety concerns over GW501516 and potentially other drugs in the class have emerged. Of particular relevance are two abstracts from GSK showing that GW501516 causes cancer in rats (6) and mice (7) after 104 weeks of dosing. Although, neither of these stu

Journal article

Kirkby NS, Akhmedov D, Berdeaux R, Mitchell JAet al., 2018, Bioluminescent Imaging of Tissue From Creb Reporter Mice Reveals the Endothelium as the Principle Site of Vascular Prostacyclin Sensing, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Kirkby NS, Akhmedov D, Shala F, Berdeaux R, Mitchell JAet al., 2018, The Right Heart is Specifically Targeted by Intravenous Administration of Treprostinil: Implications for Our Understanding of How Prostacyclin Drugs Work to Treat Pulmonary Arterial Hypertension, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Mitchell JA, Shala F, Elghazouli Y, Armstrong PC, Vadgama A, Herschman HR, Kirkby NSet al., 2018, Renal or Vascular Deletion of COX-2 Increases Thrombotic Tone: Relevance to Cardiovascular Side Effects of Non-Steroidal Anti-Inflammatory Drugs, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Mitchell JA, Shala F, Elghazouli Y, Herschman HR, Kirkby NSet al., 2018, Systemic Anti-Thrombotic Protection by a Non-Endothelial COX-1 / Prostacyclin Pathway, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Kawai R, Ahmetaj-Shala B, Shih CC, Marei I, Bhatti K, Kirkby NS, Mitchell JAet al., 2018, Development of a human autologous 3-cell cytokine release assay that models the vascular wall in vitro, 54th Congress of the European-Societies-of-Toxicology (EUROTOX) - Toxicology Out of the Box, Publisher: ELSEVIER IRELAND LTD, Pages: S114-S114, ISSN: 0378-4274

Conference paper

Ahmetaj-Shala B, Olanipekun M, Tesfai A, MacCallum N, Kirkby N, Qunilan G, Shih C-C, Kawai R, Mumby S, Paul-Clark M, Want E, Mitchell JAet al., 2018, Development of a novel UPLC-MS/MS-based platform to quantify amines, amino acids and methylarginines for applications in human disease phenotyping, Scientific Reports, Vol: 8, ISSN: 2045-2322

Amine quantification is an important strategy in patient stratification and personalised medicine. This is because amines, including amino acids and methylarginines impact on many homeostatic processes. One important pathway regulated by amine levels is nitric oxide synthase (NOS). NOS is regulated by levels of (i) the substrate, arginine, (ii) amino acids which cycle with arginine and (iii) methylarginine inhibitors of NOS. However, biomarker research in this area is hindered by the lack of a unified analytical platform. Thus, the development of a common metabolomics platform, where a wide range of amino acids and methylarginines can be measured constitutes an important unmet need. Here we report a novel high-throughput ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) platform where ≈40 amine analytes, including arginine and methylarginines can be detected and quantified on a molar basis, in a single sample of human plasma. To validate the platform and to generate biomarkers, human plasma from a well-defined cohort of patients before and after coronary artery bypass surgery, who developed systemic inflammatory response syndrome (SIRS), were analysed. Bypass surgery with SIRS significantly altered 26 amine analytes, including arginine and ADMA. Consequently, pathway analysis revealed significant changes in a range of pathways including those associated with NOS.

Journal article

Mitchell JA, Knowles RB, Kirkby NS, Reed DM, Edin ML, White WE, Chan MV, Longhurst H, Yaqoob MM, Milne GL, Zeldin DC, Warner TDet al., 2018, Letter by Mitchell et al Regarding Article, "Urinary Prostaglandin Metabolites: An Incomplete Reckoning and a Flush to Judgment"., Circulation Research, Vol: 122, Pages: e84-e85, ISSN: 0009-7330

Journal article

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