january 2006 - bscr · 2014. 11. 17. · dr michael j. curtis cardiovascular research rayne...

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The Bulletinof

The British Society for Cardiovascular ResearchRegistered Charity Number: 1011141

Vol. 19 No. 1January 2006

www.bscr.org

The BSCR is sponsored by

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The BulletinThe Publication of The British Society for Cardiovascular Research

Editors

Dr Helen MaddockApplied Human Physiology

School of Science and EnvironmentJames Starley Building, Coventry University

Priory StreetCoventry CV1 5BF

Tel: 024 76 888163 Fax: 024 76 888702E-mail: [email protected]

Dr Nicola SmartMolecular Medicine UnitInstitute of Child Health

30 Guilford StreetLondon WC1N 1EH

Tel.: 020 7242 9789 ext. 0733 Fax: 020 7404 6191E-mail: [email protected]

Chairman

Professor David EisnerUnit of Cardiac Physiology

1.524 Stopford Building, University of ManchesterOxford Road, Manchester M13 9PT

Tel.: 0161 275 2702 Fax: 0161 275 2703E-mail: [email protected]

Secretary

Professor Barbara McDermottDepartment of Therapeutics and Pharmacology

The Queen's University of BelfastWhitla Medical Builiding

97 Lisburn RoadBelfast BT9 7BL

Tel.: 028 90 272242/335770 Fax: 028 9043 8346E-mail: [email protected]

Treasurer

Dr Michael J. CurtisCardiovascular Research

Rayne Institute, St. Thomas' HospitalLondon SE1 7EH

Tel.: 020 7188 1095 Fax: 020 7188 3902E-mail: [email protected]

BAS Representative

Dr Chris NewmanClinical Sciences CentreUniversity of Sheffield

Northern General HospitalHerries Road

Sheffield S5 7AUTel: 0114 271 4456 Fax: 0114 261 9587

E-mail: [email protected]

CommitteeDr Andrew Baker

BHF Glasgow Cardiovascular Research CentreDivision of Cardiovascular and Medical Sciences

University of Glasgow, Western InfirmaryGlasgow G11 6NT

Tel: 0141 211 2100/2116 Fax: 0141 211 1763E-mail: [email protected]

Dr Katrina BicknellSchool of Pharmacy

The University of ReadingPO Box 228, Whiteknights

Reading, Berkshire RG6 6AJUnited Kingdom


Dr Barbara CasadeiUniversity Department of Cardiovascular Medicine

John Radcliffe Hospital,Oxford OX3 9DU

Tel: 01865 220132 Fax: 01865 768844E-mail: [email protected]

Dr Andrew GraceSection of Cardiovascular Biology

Department of Biochemistry, University of CambridgeTennis Court Road

Cambridge CB2 1QWTel: 01223 333631 Fax: 01223 333345


Dr Gillian A. GrayUniversity of Edinburgh

Endothelial Cell Biology and Molecular Cardiology GroupCentre for Cardiovascular Science

Queen’s Medical Research Institute,47 Little France Crescent,

Edinburgh EH16 4TJTel: 0131 242 9213


Dr Cathy HoltCardiovascular Research Group

1.305 Stopford Building, University of ManchesterOxford Rd, Manchester M13 9PT


Dr Chris JacksonBristol Heart InstituteUniversity of Bristol

Level 7, Bristol Royal InfirmaryBristol BS2 8HW.

Tel/Fax: 0117 928 2534E-mail: [email protected]

Dr Nicola KingBristol Heart Institute, University of Bristol,

Level 7, Bristol Royal Infirmary,Bristol BS2 8HW.

Tel: 01179 282208 Fax: 01179 283581E-mail: [email protected]

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Editorial 3

Review: 'Hypoxia-Inducible Factor-1 and Cardiovascular Disease'by Dr Sarah Walsh and Professor Christopher Pugh 4

Mini Review by BSCR Prize Winner Dr Enca Martin-Rendon: 'Hypoxia and Cardiac Repair' 12

Travel Report: The American Heart Association Scientific Sessions 2005, Dallas, Texas 16by Daniel Stuckey

BSCR Spring 2006 Meeting: 'Cardiovascular Genomics' Final Programme 20

Cardiovascular Related Meetings 22

British Heart Foundation Grants 24

Cardiovascular Related Wellcome Trust Grants 27

BSCR Spring 2006 Meeting: 'Cardiovascular Genomics' 28

Editorial

Helen Maddock and Nicola Smart

Cover artwork copyright Anthony Wright, 1997Cover design copyright Siân Rees and Anthony Wright, 1997

Contents

Happy New Year and Welcome to the January 2006 issue of The Bulletin!

In this issue, we bring you a review article on the function and regulation of Hypoxia-Inducible Factor-1inthe physiology and pathophysiology of the Cardiovascular system. The authors, Dr Sarah Welsh and ProfessorChristopher Pugh of the University of Oxford, speculate on the potential for HIF-1 based therapies to combatischaemic heart disease.

At the Society's Autumn meeting in London, Dr Enca Martin-Rendon was awarded the BSCR Prize for bestposter presentation. Enca presents "Hypoxia and Cardiac Repair", a brief review of the work carried out at the StemCell Reasearch Laboratory, Oxford, in collaboration with the Cardiac Metabolism Research Group at the University.

Continuing the theme of stem cell based therapies, Daniel Stuckey focuses on the subject in his report of therecent American Heart Association meeting in Dallas. Daniel provides a comprehensive overview of the stem cellpresentations and selected abstracts, highlighting the recent succcess and continued difficulties associated with the useof stem cells and the promise that they hold for cardiac regeneration.

The full programme for the forthcoming BSCR Spring Meeting "Cardiovascular Genomics" is announced in thisissue. The meeting, to be held at the Wellcome Trust Sanger Institute, has been organised by Drs Andrew Grace, JaneRogers and Willem Ouwehand and further details for those interested in attending can be found on the back cover.

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INTRODUCTIONPhysiological systems that maintain oxygen

homeostasis are among the most extensively developed,reflecting the body’s constant and absolute requirementfor oxygen. The ability to sense and respond to changesin oxygenation, therefore, represents a fundamentalproperty of all mammalian cells. In order to maintainoxygen homeostasis, mammals have developed anelaborate array of adaptive responses ranging fromchanges in ventilation and cardiac output to changes ingene expression. The steady state represents a balancebetween the requirement for oxygen as an energysubstrate, the costs of providing this oxygen and theinherent risk of oxidative damage to cellularmacromolecules. Molecular studies have begun todelineate the basis for a variety of cellular and systemicmechanisms for oxygen homeostasis, of which thetranscription factor hypoxia-inducible factor-1 (HIF-1) has been shown to be a master regulator (reviewedin (1)).

THE HYPOXIA-INDUCIBLETRANSCRIPTION FACTOR

Molecular and cellular biology of HIFHIF-1 controls the expression of more than 70

target genes whose protein products play critical rolesin acute and chronic adaptation to low oxygen. Thesegenes encode proteins involved in erythropoiesis(erythropoietin), angiogenesis (VEGF, plasminogenactivator inhibitor-1, VEGF-receptor FLT-1),glycolysis (Aldolase A and C, enolase, GLUT 1 and 3,hexokinase 1 and 2, glyceraldehyde-3-phosphate-

dehydrogenase, lactate dehydrogenase,phosphofructokinase), promotion of cell survival(adrenomedulin, IGF-2, IGF-binding proteins 1, 2 and3) and inhibition of apoptosis (IGF-2, IGF-bindingproteins 1, 2 and 3, NIP3) (see table in (2)). Indeed,increased HIF-1 transcription factor activity increasesvascularisation and energy metabolism, whereas lossof HIF-1 activity dramatically suppresses theseresponses (3,4).

HIF-1 is a heterodimer consisting of an oxygen-regulated alpha subunit (HIF-1α) and a constitutivelyexpressed beta subunit (HIF-1β, also known as theAryl Hydrocarbon Nuclear Translocator, or ARNT).Both subunits are basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain proteins in which DNAbinding and dimerisation is mediated by the basic HLHdomains, whilst the PAS domain is involved in dimerformation and transactivation (5). The transactivationdomain (TAD) of HIF-1α has been shown to bind co-activator proteins p300/CBP, SRC-1 and TIF2,whereas the TAD of HIF-1β appears to be dispensablefor the activity of the HIF-1 complex. Interestingly,two additional members of the HIF-1α family,designated HIF-2α (also known as endothelial PASdomain protein-1 (EPAS1), or MOP2) and HIF-3α(also identified as inhibitory PAS protein, IPAS) havealso been identified (6-11). HIF-2α is highly similar toHIF-1α in structure and function although it maypreferentially activate a different set of genes (12).Although HIF-3α exhibits conservation with HIF-1αand HIF-2α in the HLH and PAS domains and

Hypoxia-Inducible Factor-1 andCardiovascular Disease

by Sarah J. Welsh and Christopher W. PughUniversity of Oxford

The ability to sense and respond to changes in oxygenation is a fundamental property of allmammalian cells. Research over the past decade has produced dramatic insights into themolecular mechanisms underlying oxygen homeostasis during both normal and pathologicalconditions. Hypoxia-inducible factor-1 (HIF-1) is an essential component in determining thetranscriptional response of tissues as oxygen levels decrease, and could prove to be an importanttarget for drug development for cardiovascular disease, in which hypoxia plays a central role.

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dimerises with ARNT, it does not possess a hypoxia-inducible transactivation domain. Transient transfectionstudies suggest that it may be a negative regulator ofhypoxia-inducible gene expression (10).

Regulation of HIF-1The HIF-1 pathway is shown in Figure 1

(shown over the page). HIF-1β is a nuclear proteinwhich is constitutively expressed independently ofoxygen concentration. In contrast, alpha subunits arecytoplasmic proteins whose expression is maintainedat low levels in most cells under normoxic conditions.The HIF-1α gene promoter contains recognition sitesthat bind several ubiquitous transcriptional activatorsincluding Sp-1, AP-1, AP-2 and NF-1, causing thegene to be constitutively expressed. In addition,although the global protein translation rate is significantlyreduced in cells during hypoxic stress, the rate of HIF-1á protein synthesis does not appear to becompromised. This is most likely related to the presenceof an efficient internal ribosome entry site (IRES) in theHIF-1α mRNA, ensuring its translation is cap-independent during hypoxia (13).

However, in well oxygenated conditions, alphasubunits are continuously degraded by the ubiquitin-proteasome system (14,15) with a half-life of less than1 minute (16). Oxygen-dependent prolyl hydroxylases(PHDs) modify specific proline residues (402 and 564in human HIF-1α) (reviewed in (17)) allowing bindingof the von Hippel Lindau protein (pVHL). pVHLrecruits a ubiquitin-protein ligase complex containingelongin B, elongin C, cullin 2 and RBX1 resulting inubiquitination and degradation by the 26S proteosomepathway (18,19). A report that recognition of HIF-1αby pVHL is facilitated by acetylation at lysine residue532 by the ARD1 acetyltransferase (20) has beenrefuted by subsequent work (21).

Three prolyl hydroxylases (PHD1, 2 and 3) havebeen identified in mammalian cells and shown to useoxygen as a substrate to generate 4-hydroxyproline (22)(reviewed in (23)). Under hypoxic conditions, oxygenbecomes limiting for prolyl hydroxylation resulting indecreased ubiquitination and degradation of HIF-ásubunits which accumulate and translocate to the nucleuswhere they heterodimerize with HIF-1β subunits. Theresultant product is an active HIF-1 protein that bindsto specific HREs present in target genes, ultimatelyactivating transcription of these genes. Studies in HeLacells have shown a two-fold increase in HIF-1transactivation as the oxygen concentration declinedfrom 20 to 6% and then a 10-fold increase between 6

and 0.5% oxygen (24).Remarkably, the ability of HIF-1 to activate

transcription under normoxic conditions is preventedby another oxygen regulated hydroxylase, factorinhibiting HIF-1 (FIH-1) (25) which hydroxylatesasparagine residue 803 within the TAD of HIF-1α(26,27), disrupting its interaction with the transcriptionalco-activator p300/CBP (28). As with the prolylhydroxylases, asparagine hydroxylation is inhibitedunder hypoxic conditions, allowing the p300/CBPcomplex to bind to HIF-1α.

Further work has demonstrated additionalcomplexity in the regulation of the HIF-1 pathway. Forexample, HIF-1 activation induces several negativefeedback mechanisms. Induction of CITED-2 by HIF-1 modulates the interaction between HIF-α and p300/CBP co-activators (29); induction of an anti-sense HIFtranscript reduces HIF mRNA levels (30) and hypoxicinduction of PHD2 and PHD3 protein levels leads toenhanced HIF prolyl hydroxylation, and thus clearance(31). In addition, a variety of factors including growthfactors (PI3K, MAPK), heat-shock proteins (HSP-90), redox proteins (thioredoxin/thioredoxin reductase)and DNA damage response proteins (P53, MDM2)also modulate the activity of the HIF pathway (reviewedin (32)).

PHYSIOLOGICAL ROLE OF HIF-1

Role of HIF-1 in developmentKnockout studies show that HIF-1α, HIF-2α

and HIF-1β are all required for normal mousedevelopment (33-40). Knockout studies with HIF-3αand the PHDs have not been reported yet.Homozygous targeted inactivation of the mouse HIF-1α gene resulted in impaired extra- and intra-embryonicvessel formation, defective neural tube closure, andincreased mesenchymal cell death leading to embryonicdeath between E9.5 and E10.5 (35,36,40-42). Incontrast, the effect of homozygous targeted inactivationof the gene encoding HIF-2α was less severe and morevariable in its effects on the developing cardiovascularand respiratory systems (37-39). These embryos diedfrom defective catecholamine metabolism andbradycardia, suffered from defects in neonatal lungmaturation, or developed a syndrome of multi-organpathology and biochemical abnormalities. Only onegroup reported defects in the yolk sac vasculature whichwas rescued by HIF-2α. However, the use of adominant-negative HIF mutant (HIFdn) that inhibited

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mRNAHIF-1

VEGFFGF-2iNOSothers

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p300CBPAsn hydroxylase

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Proteasomaldegradation

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Figure 1. Simplified diagram of the HIF-1 pathway

activity of both HIF-1 and HIF-2 confirmed an essentialrole for endothelial hypoxia-inducible factors in theformation of the heart, in angiogenic sprouting, and inthe remodelling of the embryonic vascular system (43).

In wild-type mouse embryos, HIF-1α isexpressed in the early heart and in cultured ventricularmyocytes and HIF-1α expression increasesdramatically between E8.5 and E9.5 (44). A variety ofmechanisms have been proposed to explain how theabsence of HIF-1α leads to cardiovascularmalformations. Compernolle et al have suggested thatthe cardiac disturbances observed in HIF-1α-/-embryos may be contributed to by reduced expressionof myocyte enhancer factor 2C (MEF2C) and eHAND(40).

Ang-1, Ang-2, TIE2 and MEF2C have all beenimplicated in maturation and stabilization of the primitivevascular network by affecting periendothelial cells (40).Levels of these factors were all decreased in HIF-1α-/- embryos although levels of other angiogenic factorswere either unchanged (TGF-β) or slightly increased(PDGF-B, VEGF). Interestingly HIF-dependenteffects on the various receptors for these growth factorshave also been reported (45). Additionally, the

hypoplastic pharyngeal arch, aortic outflow tract andcephalic blood vessel abnormalities observed in HIF-1α-/- embryos may be explained by impaired migrationof neural crest cells related to insufficient levels ofsemaphorin-3A (40).

Role of HIF-1 in post-natal physiologyThe principal medical consequences of chronic

hypoxia include polycythemia, pulmonary hypertension,and weight loss, all of which are associated with greatlyincreased mortality (46-48). Laboratory animalssubjected to decreased ambient O2

concentrationsmanifest similar physiological responses ((49) andreferences within). Polycythemia is attributable toincreased plasma levels of erythropoietin, whichenhances survival of erythroid progenitor cells (reviewedin (50)). The pathophysiology of hypoxic pulmonaryhypertension is more complex and involvesvasoconstriction as well as neomuscularization andthickening of the media and adventitia of pulmonaryarterioles (51). Weight loss under conditions of chronichypoxia may reflect multiple changes in cardiovascularfunction, hormone production, energy metabolism, andother aspects of cellular and systemic physiology.

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The analysis of heterozygous knockout mice andcell lines has definitively demonstrated that the HIF-1pathway plays a significant role in physiologicalresponses to chronic hypoxia. Despite the presence ofone normally functioning allele, Hif1α+/– mice wereimpaired in the development of polycythemia, rightventricular hypertrophy, pulmonary hypertension (52),vascular remodelling (52,53), carotid body sensing ofarterial oxygen (54) and hypoxia-induced myocardialpreconditioning (55). In addition, Hif1α+/– mice alsolost more weight than Hif1α+/+ mice when exposed to10% oxygen for several weeks (52). HIF-1 also playsan essential role in immunity as myeloid cells from HIF-1α+/- mice show a complete inability to respond toinflammatory stimuli (56), and B lymphocytedevelopment and T lymphocyte activation are alsoimpaired (57,58).

Role of HIF-1 in cardiovascular pathologyHIF-1 also plays an important role in the patho-

physiology of myocardial infarction. When the myo-cardium is deprived of blood, a process of ischaemia,infarction and myocardial remodelling is initiated. Clini-cal data suggests that the HIF-1 pathway representsone of the first adaptations of the myocardium to a dep-rivation of blood (59) and may persist even late afterthe acute event, possibly indicating persistent ischae-mia (60). Similarly, HIF activation has been demon-strated in experimental myocardial infarction (55) whereadaptive changes in HIF hydroxylases also occur(Willam et al., unpublished data).

Additional evidence that the HIF-1 pathway isinvolved in the adaptive response to ischemia has beenshown by the critical involvement of HIF-1α in the pro-tection of heart tissue from post-ischemic injury (55).Exposure of wild-type mice to intermittent hypoxia re-sulted in protection of isolated hearts against ischemia-reperfusion injury 24h later. Significantly, cardiac pro-tection was lost in HIF-1α+/- mice. The precisemechanism for protection by HIF-1α is unclear but bothNOS2 (61) and EPO (55) have been suggested to playa role.

The coronary artery collateral circulation is ben-eficial in protecting against myocardial ischemia/infarc-tion and necrosis due to coronary artery stenosis andacute coronary occlusion (62-64). Although initially itwas believed that all coronary collaterals were pre-formed and opened up only at times of need, it is nowaccepted that collaterals can form by the process ofneoangiogenesis (reviewed in (65)). However, in theclinical setting wide inter-patient differences are ob-

served in the degree of collateral formation, such thatonly 50% of patients with coronary artery stenosis de-velop collaterals (64). Interestingly, although normoxiclevels of VEGF are not significantly different betweenpatients with different degrees of collateral vessel for-mation, the presence of collaterals correlates with theability to induce VEGF in response to hypoxia (66).Hypoxic induction of VEGF was shown to occur in aHIF-1 dependent manner (67) and variations in HIF-1α genotype have been reported to influence the de-velopment of coronary artery collaterals in patients withsignificant coronary artery disease (68). Other studieshave found an age-related decrease in the expressionof HIF-1α in both mouse and human hearts (69) cor-relating with the decreased ability to tolerate and adaptto ischaemic vascular disease in the elderly (70).Hypercholestrolaemia (71), hypertension (72,73), ciga-rette smoking (74) and diabetes (75) are associatedwith decreased expression of the HIF target genesVEGF and basic fibroblast growth factor (bFGF).However, it is unclear whether these actions are medi-ated via effects on the HIF pathway.

POTENTIAL FOR HIF-1 BASED THERAPY OFISCHAEMIC DISEASE

It is clear that HIF-1 regulates O2 homeostasisby controlling both the establishment of key physiologi-cal systems during embryogenesis and their subsequentutilization throughout life. Ischemia arises when tissuedemand for energy substrates (oxygen and glucose) isnot matched by supply, usually due to impairedperfusion. The formation of a functionally intact micro-vasculature requires the coordinated activation of sev-eral genes. Stimulation of the HIF pathway has theadvantage of activating a master gene switch that re-sults in a broad and coordinated downstream reaction.In addition to co-ordinating angiogenesis, the HIF path-way could provide a route to metabolic salvage (byup-regulating glycolytic capacity) and, in some cases,reducing energy demand by affecting cell growth /apoptosis / necrosis decisions. Several strategies offerthe potential of modulating the HIF-1-dependent re-sponse to ischemia/hypoxia. Indeed, the delayed pre-conditioning response, where exposure of a tissue ororgan to one or more brief episodes of ischemia pro-vides protection against subsequent prolonged ischemia,may be mediated via HIF.

However, caution is required when manipulatinga finely balanced physiological system. Approacheswill ultimately have to take account of the various feed-back mechanisms modulating the system and the time

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course of interventions may be critical. Care will beneeded in targeting therapy to ischaemic areas sinceuncontrolled effects in other sites may be deleterious.A further complexity is that it has recently become ap-parent that activation of the different HIF-α isoformssometimes has discordant biological effects, so it maybe necessary to target a specific isoform to gain benefitin a particular tissue (12,76,77).

Despite these theoretical concerns, severalstudies have used gene therapy to over-expressstabilised or constitutively activated HIF and therebymodulated downstream genes. Such approaches haveallowed the generation of increased dermal capillarieswhen HIF activity was increased in the skin (78),improved vascularity in a hind limb ischaemia model(79-82) and increased myocardial blood flow in a ratacute myocardial infarction model. In general, effectshave been better than those seen with VEGF-basedgene therapy which tends to produce leaky immaturevessels and tissue oedema (83).

An alternative method for modulating HIF-1pathway activity is to target the processes involved ininactivating HIF in normoxia. Peptide bound inhibitorsof the HIF/VHL interaction have been shown to pro-mote blood vessel growth and induce genes relevant tometabolic adaptation (84). Inhibition of the HIFhydroxylases using small molecule inhibitors holds prom-ise for induction of HIF-1 activity. Interestingly, ad-ministration of a 2-oxoglutarate analogue increasedcapillary to fibre ratios in a hind limb ischaemia model(85). Further studies report the use of newer, and per-haps more specific, inhibitors which also show poten-tial beneficial effects (86).

CONCLUSIONThe rapid progress made in recent years regarding

the role of HIF-1 in the cellular response to hypoxia/ischemia is remarkable. It is clear that HIF-1 plays acritical role in both normal and pathological responsesto hypoxia and represents an exciting target for thera-peutic intervention in the future. Several approachesare currently under investigation and given the currentrate of accumulation of data, it will not be long beforethis knowledge is taken forwards into the clinic.

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England Journal of Medicine 342(9), 626-63360. Parisi, Q., Biondi-Zoccai, G. G., Abbate, A., Santini,D., Vasaturo, F., Scarpa, S., Bussani, R., Leone, A.M., Petrolini, A., Silvestri, F., Biasucci, L. M., and Baldi,A. (2005) International Journal of Cardiology 99(2),337-33961. Xi, L., Tekin, D., Gursoy, E., Salloum, F.,Levasseur, J. E., and Kukreja, R. C. (2002) Am JPhysiol Heart Circ Physiol 283(1), H5-1262. Habib, G. B., Heibig, J., Forman, S. A., Brown, B.G., Roberts, R., Terrin, M. L., and Bolli, R. (1991)Circulation 83(3), 739-74663. Hansen, J. F. (1989) Am Heart J 117(2), 290-29564. Baroldi, G., and Giuliano, G. (1986) Can J CardiolSuppl A, 248A-254A65. Breier, G. (2000) Semin Thromb Hemost 26(5),553-55966. Schultz, A., Lavie, L., Hochberg, I., Beyar, R.,Stone, T., Skorecki, K., Lavie, P., Roguin, A., and Levy,A. P. (1999) Circulation 100, 547-55267. Levy, A. P., Levy, N. S., Loscalzo, J., Calderone,A., Takahashi, N., Yeo, K.-T., Koren, G., Colucci, W.S., and Goldberg, M. A. (1995) Circulation Research76, 758-76668. Resar, J. R., Roguin, A., Voner, J., Nasir, K.,Hennebry, T. A., Miller, J. M., Ingersoll, R., Kasch, L.M., and Semenza, G. L. (2005) Chest 128(2), 787-79169. Rohrbach, S., Simm, A., Pregla, R., Franke, C.,and Katschinski, D. M. (2005) Biogerontology 6(3),165-17170. Frishman, W. H. (1993) South Med J 86(10),2S29-3771. Van Belle, E., Rivard, A., Chen, D., Silver, M.,Bunting, S., Ferrara, N., Symes, J. F., Bauters, C.,and Isner, J. M. (1997) Circulation 96(8), 2667-267472. Kyriakides, Z. S., Kremastinos, D. T.,Michelakakis, N. A., Matsakas, E. P., Demovelis, T.,and Toutouzas, P. K. (1991) Am J Cardiol 67(8), 687-69073. Karpanou, E. A., Vyssoulis, G. P., Skoumas, J. N.,Zervopoulos, G. A., Moundaki, V. S., and Toutouzas,P. K. (1988) J Hypertens Suppl 6(4), S151-15374. Heinle, R. A., Levy, R. I., and Gorlin, R. (1974)Am J Cardiol 33(1), 12-16

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75. Roguin, A., Nitecki, S., Rubinstein, I., Nevo, E.,Avivi, A., Levy, N. S., Abassi, Z. A., Sabo, E., Lache,O., Frank, M., Hoffman, A., and Levy, A. P. (2003)Cardiovasc Diabetol 2, 1876. Warnecke, C., Zaborowska, Z., Kurreck, J.,Erdmann, V. A., Frei, U., Wiesener, M., and Eckardt,K. U. (2004) FASEB Journal 18(12), 1462-146477. Hu, C.-J., Wang, L.-Y., Chodosh, L. A., Keith,B., and Simon, M. C. (2003) Molecular andCellularBiology 23(24), 9361-937478. Elson, D. A., Thurston, G., Huang, L. E., Ginzinger,D. G., McDonald, D. M., Johnson, R. S., and Arbeit,J. M. (2001) Genes & Development 15(19), 2520-253279. Kelly, B. D., Hackett, S. F., Hirota, K., Oshima,Y., Cai, Z., Berg-Dixon, S., Rowan, A., Yan, Z.,Campochiaro, P. A., and Semenza, G. L. (2003) CircRes 93(11), 1074-108180. Triezenberg, S. J., LaMarco, K. L., and McKnight,S. L. (1988) Genes Dev 2(6), 730-74281. Shyu, K. G., Wang, M. T., Wang, B. W., Chang,C. C., Leu, J. G., Kuan, P., and Chang, H. (2002)Cardiovascular Research 54(3), 576-58382. Vincent, K. A., Shyu, K. G., Luo, Y., Magner, M.,Tio, R. A., Jiang, C., Goldberg, M. A., Akita, G. Y.,Gregory, R. J., and Isner, J. M. (2000) Circulation102, 2255-2256183. Flamme, I., von Reutern, M., Drexler, H. C., Syed-Ali, S., and Risau, W. (1995) Dev Biol 171(2), 399-414

Sarah J. Welsh1 and Christopher W. Pugh1,2

1University of OxfordOxfordUK

2Corresponding authorProfessor C.W. PughThe Henry Wellcome Building for MolecularPhysiology, Roosevelt DriveOxford OX3 7BNUKEmail: [email protected]: +44 (0)1865 287786Fax: +44 (0)1865 287787Email: [email protected]

84. Willam, C., Masson, N., Tian, Y. M., Mahmood,S. A., Wilson, M. I., Bicknell, R., Eckardt, K. U.,Maxwell, P. H., Ratcliffe, P. J., and Pugh, C. W. (2002)Proceedings of the National Academy of Sciences,USA 99(16), 10423-1042885. Milkiewicz, M., Pugh, C. W., and Egginton, S.(2004) Journal of Physiology 560(1), 21-2686. Warnecke, C., Griethe, W., Weidemann, A.,Jurgensen, J. S., Willam, C., Bachmann, S.,Ivashchenko, Y., Wagner, I., Frei, U., Wiesener, M.,and Eckardt, K.-U. (2003) FASEB Journal 17, 1186-1188

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Hypoxia and Cardiac RepairEnca Martin-Rendon1*, Corinne Willmott1, Sarah Hale1, Carolyn Carr2, Daniel Stuckey2, Louise Tatton1,Kieran Clarke2 and Suzanne M. Watt1. 1Stem Cell Research Laboratory, National Blood Service,Oxford-Centre and 2Cardiac Metabolism Research Group, University Laboratory of Physiology,University of Oxford.

* Dr Enca Martin-Rendon was the recipient of the BSCR Prize for the Best Poster Presentation at the Autumn 2005BSCR Meeting held at St Thomas' Hospital, London.

A promising novel approach for treatingmyocardial infarction and heart failure is stem/progenitorcell grafting in the damaged myocardium. Successfulstem cell transplantation requires that the transplantedcells home, migrate and engraft efficiently at sites ofinjury. An area of interest of the Stem Cell ResearchLaboratory (Table 1) is the effect of tissue hypoxia,which is found in ischaemic heart disease, burns,tumours and bone marrow on the maintenance, homingand engraftment of stem cells. Since hypoxia within theischaemic tissue is a potent stimulus forneovascularisation, our hypothesis is that key genesinvolved in the proliferation/survival and migration/homing of stem cells to or within specific sites of injuryare regulated by hypoxia (e.g., the expression of thechemokine CXCL12 and its receptor CXCR4 are bothregulated by hypoxia). We are currently defining themolecular signature of primitive CD133+ endothelialprogenitor cells and their associated mesenchymalprogenitor cells, isolated from umbilical cord blood(UCB) and bone marrow respectively, as they switch

from normoxic to hypoxic conditions (Figure 1). Bonemarrow mesenchymal stem cells (MSC) are multipotentprogenitors that have the potential to generateosteoblasts, chondrocytes, adipocytes, endothelial andmuscle cells and the bone marrow stroma that supportshaemopoiesis and blood vessel formation. Using cDNAarray hybridisation we have demonstrated thatapproximately 231 genes are differentially expressed(> 1.5-fold change at the mRNA level) when exposedto hypoxia over time, with 133 genes being regulatedat 24h. A large proportion of these genes are unknownor have unknown function and 16.4% of the total 133genes are involved in cell proliferation and cell survival.Examples of genes found to be regulated by hypoxia inMSC are the glucose transporter (GLUT)-1, vascularendothelial growth factor (VEGF) and the pro-apoptotic factor BNIP3.

Our laboratories have established the left anteriordescending (LAD) artery ligation model of myocardialinfarction in the rat. Rat bone marrow derived stromalcells (MSC) were isolated by adherence to plastic andcharacterized by the expression of specific cell surfacemarkers using flow cytometry (Figure 2). They arepositive for CD90 and negative for CD45R, CD11b/c, CD31 and CD4. Cells were transduced with a GFP-expressing lentiviral vector system and labeled with ironoxide particles (IFPs). Double-labelled cells wereexposed to normoxia (21% oxygen) or hypoxia (1.5%oxygen) for 24 hours prior to being injected into theinfarct periphery of rat hearts. Cine MRI was used totrack the transplanted bone marrow stromal cells oversixteen weeks and to monitor cardiac function. Asignificant increase in cardiac output was observed inanimals treated with MSC exposed to normoxia andhypoxia, compared with control animals and GFPpositive cells were detected in the infarct region. Our

SCRL Major Research Activities

• Umbilical cord blood (UCB) collection for research programmes

• GMP facilities for cell therapies

• Isolation, characterisation and differentiation of human and rodent adult stem cells

• Molecular signature of human stem/progenitor cells

• Gene/drug discovery platform for stem cell therapies

• Tissue hypoxia (e.g. heart disease, tumours, burns and bone marrow)















Table 1

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results suggest that MSC grafting contributes to theimprovement in cardiac function.

We are currently focusing our studies onunderstanding the underlying mechanisms by whichMSC improve cardiac function.

Conclusion: We have demonstrated that MSCproliferate better when exposed to hypoxia thannormoxia in culture and that these cells improve cardiacfunction to a similar degree. Exposure to low oxygen inculture may be useful in increasing MSC numbers priorto transplantation and it may also improve MSC survivaland cell grafting in the damaged heart tissue.

This work is supported by the National Blood

Authority (NBA) and the British Heart Foundation(BHF).

The Stem Cell and Immunotherapies (SCI)Function in the National Blood Service is led by Dr.Suzanne M. Watt (National Head of SCI). The SCIDepartment is composed of nine SCI ServiceLaboratories in the country and the Stem Cell ResearchLaboratory in Oxford which is involved in basic andtranslational research (Drs. S. M. Watt, E. Martin-Rendon and J. Smythe). The SCI laboratories possessMHRA and JACIE accredited GMP facilities thatcurrently provide expertise for processing, manipulatingand storing cellular products (bone marrow, peripheral

-tubulin

HIF

pO2 1.5% 21%

MSC

21.6%16.4%11.9%11.9%11.2%9.7%9.5%6%

3.7%1.5%1.5%

0.74%0.74%

UnknownCell proliferation/survivalSignal transductionCell adhesion/motilityMetabolismProtein metabolismRegulation of transcriptionTransportNucleic Acid metabolismStructural proteinsImmune responseBlood coagulationSex determination

% of genesBiological Process (GO)

Fold

-incr

ease

in c

ell n

umbe

r

Seeding density (x104/cm2)

0

0.5

1

1.5

2

2.5

3

3.5

0.5 1 2 5

(A) (B)

(C) (D)

-tubulin

HIF

pO2 1.5% 21%

MSC

21.6%16.4%11.9%11.9%11.2%9.7%9.5%6%

3.7%1.5%1.5%

0.74%0.74%

UnknownCell proliferation/survivalSignal transductionCell adhesion/motilityMetabolismProtein metabolismRegulation of transcriptionTransportNucleic Acid metabolismStructural proteinsImmune responseBlood coagulationSex determination

% of genesBiological Process (GO)

Fold

-incr

ease

in c

ell n

umbe

r

Seeding density (x104/cm2)

0

0.5

1

1.5

2

2.5

3

3.5

0.5 1 2 5

(A) (B)

(C) (D)

Figure 1: Differential expression of genes regulated by hypoxia in MSC. Increase in MSC numberafter culturing at different densities in normoxia (21% oxygen) or hypoxia (1.5% oxygen) for 24 hours.Proliferation is promoted in hypoxia at lower seeding densities (A). Western blot analysis of hypoxia induciblefactor (HIF)-1 in total cell extracts of MSC exposed to normoxia or hypoxia for 24 hours (B). Representativeimage of high density oligo array hybridised with total mRNA from MSC (C). Genes that are up-regulated byhypoxia are represented in red and genes down-regulated are represented in green. A total of 133 genes aredifferentially expressed at 24 hours in MSC. Genes are classified according to biological processes usingGene Ontology (GO) software (D).

14

blood and umbilical cord blood) for almost 40% of thebone marrow transplants in England. They are alsoinvolved in clinical trials with academic partners andNHS Trust hospitals for the delivery of cellular therapiesand could provide novel stem cell therapies to patientsin the near future.

The Cardiac Metabolism Research Group at theUniversity Laboratory of Physiology, University ofOxford is led by Prof. Kieran Clarke (Director). TheGroup has extensive experience in cardiac metabolismand magnetic resonance imaging (MRI). Recently, an11.75 T MRI system with a super-wide vertical borehas been installed in the laboratory and CINE MRIhas been developed by Prof. Clarke’s group (Prof.Kieran Clarke, Dr. C. Carr and Mr. D. Stuckey). The11.75 T MRI is one of the most powerful animal imagingsystem in the world.

Both the Stem Cell Research Group and theCardiac Metabolism Research Group are members ofthe British Collaborative on Stem Cell Repair of theHeart (Prof. John Martin, UCL, co-ordinator), a

platform for British lead scientists and clinicians toestablish co-ordinated programmes in cardiovascularstem-cell research.

(A) (B) (C) (D)

(E) (F) (G)

7%7% 90%90%

Figure 2: MSC improve cardiac function in a LAD artery ligation model of acute myocardial infarction. Rat MSC wereisolated from fresh bone marrow by adherence to plastic and further characterised by passaging them. The fibroblastic-like population devoid of haemopoietic cells was characterised by the expression of cell surface markers using flowcytometry. The cells are negative for CD11b/c, CD4, CD31 (data not shown) and CD45R (A) and positive for CD90 (B).Cells were transduced with a lentiviral vector system expressing GFP, yielding approximately 50% transduction efficiency(C). Cells were also labelled with iron fluorescent particles (D) that were taken up easily. Approximately 5x105 doublelabelled cellswere injected intramyocardially 10 minutes after ligation of the coronary artery in the infarct periphery. CineMRI was used to track the cells for a period of 16 weeks (E). At 16 weeks the animals were sacrificed and the hearts fixedfor immunohystochemical analysis. GFP-positive cells (arrows) were detected in the areas of injection (F). A significantlygreater increase (* p<0.05) in cardiac function was observed in animals injected with MSC compared to control animals(G). Hypoxic preconditioning of MSC had a similar effect and did not result in a significant improvement over normoxia (G).

Address for correspondence:

Enca Martin-Rendon, PhDStem Cell Research Laboratory

National Blood ServiceOxford Centre

The John Radcliffe HospitalHeadington

Oxford, OX3 9BQPhone: 01865 44 79 34FAX: 01865 44 79 31

e-mail: [email protected]

16

Travel Report: The American Heart AssociationScientific Sessions 2005, Dallas, Texas

13th-16th November 2005

by Daniel Stuckey, Cardiac Metabolism Research Group,University of Oxford

With over 27 000 attendees and close to 4 000abstracts presented, The American Heart AssociationScientific Sessions is about as big as scientific meetingsget. Dallas doesn’t have too much to offer as a touristdestination, a visit to the grassy knoll was not the mostexhilarating experience I’ve ever had, but we did go tothe rodeo, which certainly was an exciting and interest-ing night out, even if we didn’t totally understand whatwas going on! The conference facilities were first classas were the scientific sessions. Due to the enormity ofthe meeting, this report will focus on one of the mostoversubscribed areas of research at this years AHA,the use of stem cell therapy for cardiovascular disease.

The grassy knoll, impressive!

Although stem cell biology is a relatively new field,there are now hundreds of research groups investigat-ing ways of regenerating damaged organs using stemcells. At most points throughout this meeting there weretwo or more sessions concerned with stem cell therapyfor the cardiovascular system, and delegates regularlyhad to queue outside the doors to try to get in.

A major theme running through the basic stemcell sessions was the regenerative potential of cardiacstem cells and cardiospheres. These cells, first de-scribed by Piero Anversa’s group (Valhalla, NY) in2003, can be isolated from the heart and have the abil-

17

ity to form new cardiomyocytes and vasculature.Annarosa Leri (Valhalla, NY) presented an excellentoverview of the field, whilst abstracts presented byTateishi (Kyoto, Japan), Ruckdeschel-Smith (JohnsHopkins), Frati (Uni Parma, Italy) and Goumans(Utrecht, The Netherlands) demonstrated that thesecells could be isolated from biopsies of adult humanheart. Another recurring theme concerned the paracrinemechanism associated with the delivery of adult stemcells to damaged hearts. A report by Gnecchi, (DukeUni, NC) showed that the conditioned culture mediafrom mesenchymal stem cells transfected with Akt canimprove heart function in Langendorff perfused hearts.Mirotsou (Duke Uni, NC) identified several genes, in-cluding VEGFa, angiopoietin 4 and HGF, that wereupregulated in these Akt-MSCs and could be respon-sible for the improvements observed. Alongside theseparacrine mechanisms of improving heart function, therewere further papers showing the differentiation of stemcells into new myocytes in mice (Uemura, Cincinnati)and rats (Tanaka, Japan).

One of the most controversial areas of stem cellbiology concerns the ability of stem cells to acquire acardiomyocyte phenotype by either transdifferentiationor fusion. Two papers published in Nature in spring2004 by Murry and Balsam, strongly questioned thetransdifferentiation observed by Orlic and Anversa threeyears previously, and illustrated that a cardiomyocytephenotype was acquired by cell fusion. A further pa-per from Anversa’s group in 2005 reconfirmed theirprevious finding that new cardiomyocytes are formedby transdifferentiation, and dismissed the methodolo-gies used by their critics. This disagreement continuedwith a presentation by Dr Murry entitled “Do Stem Cellsin the Heart Truly Differentiate into Cardiomyocytes?”being heavily criticised. Unfortunately this session washeld in a tiny meeting room and I was stuck in the crowdof people outside, unable to see the fireworks!Throughout the rest of the meeting this conflict was notobviously vocalised. Now both sides of the argumentseem to believe they have proved their case withoutdoubt and moved on to actually trying to regenerate

Rodeo

18

hearts.

A translational science session of biologicalimaging introduced some interesting methodologies thatcould be used to monitor stem cell location and inte-gration. Micheal Rubart (Indianapolis) presented a twophoton microscopy technique that can measure calciumtransients in the Langendorff perfused heart. Usinghearts that had been injected with GFP+ foetalcardiomyocytes, he showed line scan images through acluster of cardiomyocytes, some derived from the do-nor and some from the host. The calcium transientswere of the same magnitude and frequency in the do-nor cells and the host cardiomyocytes, suggesting thatthese cells were functionally coupled to the host myo-cardium. When this experiment was repeated usingeither skeletal myoblasts or bone marrow derived stemcells as donor cells, integration was not observed, evenwhen the skeletal myoblasts were modified to

overexpress the gap junction protein connexin 43.Methods for non-invasive identification of stem cell in-jection sites were reviewed by Robert Lederman(NIH). He showed images from pigs where injectionsites could be followed for several weeks. The useful-ness of this technique was further illustrated later in themeeting by Dara Kraitchman (Johns Hopkins), whotracked cells in dogs, and by myself, using MRI to trackstem cells in infarcted rat hearts up to 16 weeks afteradministration. Dr Lederman also demonstrated thereal time MRI guided catheter that his group has de-veloped to permit accurate injection of stem cells intothe myocardium – “…if you can find some cells thatwork!” he added.

One of the most astonishing aspects of the fieldof stem cell therapy is not that cells isolated from theadult human heart can form new cardiomyocytes, butthat cell therapy has been in the clinic for over 3 years.Initial studies showed the feasibility and safety of stemcell based therapy given as coronary infusion or injec-tion at the time of cardiac intervention. More recentlystudies have shown beneficial effects on cardiac func-tion and perfusion. At the AHA this year the results ofa randomized, double blind, placebo controlled clinicaltrial performed at 17 centres across Germany andSwitzerland including 204 patients suffering acute myo-cardial infarction were announced. The REPAIR-AMItrial infused approximately 236 million autologous bonemarrow derived mononuclear cells 4 to 7 days postMI. The investigators found a 5.5% improvement inleft ventricular ejection fraction in the stem cell treatedgroup, compared with 3% in the control group at 4months (p = 0.014). Post hoc analysis revealed thatpatients who received infusions within five days afterMI showed less improvement in function than patientsin which infusions were performed after day five. Fur-ther it was noted that patients with the lowest ejectionfractions received the greatest benefit from cell therapy.Even though this study was not designed to answerthese questions, the results are interesting and are sup-ported by other studies, for example Perin et al previ-ously found that patients with ejection fractions of only20% at baseline could be improved to 29% four monthsafter stem cell injection.

Lunch in the sunshine outside the ConferenceCentre

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A majority of stem cell related abstracts presentedat AHA showed beneficial effects of cell therapy forthe cardiovascular system, but there were exceptions,including reduced coronary blood flow and increasedtroponin I in dogs that received coronary infusion of50x106 mesenchymal stem cells (Silva, Houston,Texas). The most notable data that dampened the eu-phoria surrounding stem cell therapy were shown onthe final day in a late breaking clinical trail session. Just72 hours after the reported success of the REPAIRAMI trail, the results of the ASTAMI trial, a similarstudy conducted in Norway, were presented. In thistrial 100 patients received coronary infusion of eithertheir own mononuclear cells, or placebo control me-dia, 4 to 8 days post MI. This study showed no signifi-cant differences in ejection fraction as measured byecho, SPECT, or cardiac MRI six months after cellinfusion. Dr Willerson (last author in one of the firststem cell clinical trials for heart disease conducted inTexas and Brazil) commented on this work and sug-gested that the data could be divided into groups withsevere and moderate infarction or into cohorts that re-ceived cells on different days after infarction, as thiswas found to increase the stem cell mediated improve-ments in heart function in the REPAIR-AMI study. Healso postulated that the extremely high level of postoperative care given to these patients may mask someof the effects of the infused cells. These studies showedthat more research is needed for a proper understand-ing of the mechanisms that lead to the functional im-provements reported in the clinical trials. In an inter-esting parallel to the basic science reports, Dr Willersonrevealed that one of the patents treated in the originalstudy in Brazil, and who had shown significant benefitfrom cell therapy, had died of causes unrelated to thestem cell therapy. Numerous pathologists had closelyexamined the heart of this patient and found evidenceof neovascularisation, and possibly newcardiomyocytes.

Further presentations of interest included the PaulDudley White International Lecture given by Prof.Stefan Neubauer (Oxford, UK) entitled, “The failingheart, an engine running out of fuel?”. Prof. Neubauerillustrated the importance of energy metabolism in the Prof. Neubauer on the big stage

heart and suggested that selective metabolic interven-tion could be an extremely important area of researchand treatment. Cardiac metabolism was also assessedin a study of subjects fed a high fat, low carbohydratediet for 2 weeks. Dr Scheuermann-Freestone (Ox-ford, UK) measured cardiac high energy phosphatesand function in normal subjects before and after tthediet using magnetic resonance. After only two days onthe diet, a significant decrease in the phosphocreatineto ATP ratio was observed, and after two weeks car-diac diastolic function was impaired.

The AHA squeezes years of research, conductedby hundreds of different groups, into just 4 days ofpresentations. With many of the major players from allfields attending, the AHA can give a unique insight intothe hot topics in all areas of cardiovascular research.By including basic, translational and clinical sciencepresentations at the same meeting, the direct effectsand outcomes of basic research can be understood. Ithoroughly enjoyed my week in Dallas, and hope to doit all again next year when AHA moves to Chicago.

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BSCR 2006 SPRING MEETINGMONDAY 27TH & TUESDAY 28TH MARCH 2006

Hinxton Hall Conference Centre, WellcomeTrust Sanger Institute, Cambridge

Cardiovascular Genomics

Organizers: Andrew Grace, Jane Rogers andWillem Ouwehand

FINAL PROGRAMMEMonday 27th March 200612.00 - 13.30 Registration and lunch

Session 1: Cardiovascular Applications of Genomics

13.30 - 13.40 Introduction and welcome

13.40 - 14.15 Hugh Watkins (Oxford)Genetics, genomics and genetical genomics

14.15 - 14.50 Calum McCrae (Boston, MA)Model Systems

14.50 - 15.25 Panagiotis Deloukas (WTSI)Sequence variation in humans and the HapMap project

15.25 - 16.00 Speaker TBDGene sequences, drug targets and drug design

16.00 - 16.15 Tea

16.15 - 17.00 Keynote Lecture Dan Roden (Vanderbilt)Cardiovascular Pharmacogenomics (TBD)

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17.00 - 18.00 Poster viewing and wine reception

20.00 Dinner, Trinity College

Tuesday 28th March 2006

Session 2: Phenotypes and Genotypes

09.00 - 09.35 Andrew Grace (Cambridge)Linking genes to function: clinical phenotypes

09.35 - 10.10 Eric Schulze-Bahr (Münster)Candidate genes for Sudden Cardiac Death

10.10 - 10.45 Aroon Hingorani (London)Biomarkers and cardiovascular disease: insights from Mendelian randomisation

10.45 - 11.15 Coffee

11.15 - 12.45 Free Communications

12.45 - 13.45 Lunch

Tuesday 28th March 2006

Session 3: Application of post-genome technologies to coronary artery disease

13.45 - 14.20 Nilesh Samani (Leicester)Candidate genes to genome-wide association studies in Coronary Disease

14.20 - 14.55 David Clayton (Cambridge)Design and analysis in genome-wide association studies

14.55 - 15.40 Application of other –omic technologiesa. Metabonomics (James Metcalfe, Cambridge)b. Proteomics (UCD, Ireland)c. Transcriptomics (Nick Watkins, Cambridge)

15.40 - 16.00 Tea

16.15 – 17.00 Keynote lecture Bruce Furie, BostonBiological aspects of arterial clot formation

17.00 Presentation of Clinical Science and BSCR Prizes

Tea and close of meeting

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Cardiovascular Related Meetings

55th Annual Scientific Session of the American College of Cardiology, 11th-14thMarch, 2006 to be held in Atlanta, USA. Contact: [email protected]; Website: http://www.acc.org/2006ann_meeting/home/home.htm

Heart Foundation Conference 2006, 23rd-25th March, 2006, Sydney, Australia. Furtherdetails may be obtained from the website: http://www.heartfoundation.com.au/2006conference

1st International Conference on Hypertension, Lipids, Diabetes and StrokePrevention Interdisciplinary and Multifactorial Approach, Paris, France. 30th March- 1st April, 2006. Enquiries: [email protected], Kenes International - GlobalCongress Organisers and Association Management Services, 17 Rue du Cendrier, PO Box1726, CH-1211 Geneva 1, Switzerland, Tel: +41 22 908 0488, Fax: +41 22 732 2850,Website: www.kenes.com/strokeprevention

Annual Scientific Conference of the British Cardiac Society, 24th-27th April, 2006,Glasgow, UK. Contact: [email protected]; Website: http://www.bcs.com/

The XXVI ISHR European Section Meeting will be held 14-17 June 2006, at theUniversity of Manchester, Manchester, UK. Enquiries: Mrs R Poulton, ScientificSecretariat, The University of Manchester, Room 1.302, Stopford Building, Oxford Road,Manchester, M13 9PI, United Kingdom. Tel: +44 161 2751628, E-mail:[email protected] or The University of Manchester, ConferCare, MeetingSecretariat, Barnes Wallis Building, Sackville Street, Manchester M60 1QD. Tel: +44 1613065068, Email: [email protected],Website: www.meeting.co.uk/confercare/ishr2006.

The XXVIIIth Annual Meeting of the ISHR - North American Section will be heldJune 13-16, 2006 at the Westin Harbour Castle in Toronto, Canada. Enquiries: Dr. PeterLiu, Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Rm 78A, 150 College Street, FitzGerald Building, Toronto, Ontariou M5S 3E2. Tel: 416-946-8543, Fax: 416-946-7545, Email: [email protected], Website:www.ishr2006.com.

Heart Failure 2006, 17th-20th June. This year's meeting will be held in Helsinki, Finland.Contact information: [email protected]

World Congress of Cardiology 2006: Joint Congress of the European Society ofCardiology and the World Heart Federation. 2nd - 6th September 2006. Barcelona,Spain. Further information can be obtained from: EUROECHO Secretariat: ESC, 2035 routedes Colles, Les Templiers - BP 179, 06903 Sophia Antipolis Cedex, France. Tel: +33 (0) 4 9294 76 00; Fax: +33 (0) 4 92 94 76 01; E-mail:[email protected]; Website: www.escardio.org

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Volume Date Deadline

19 (2) April 2006 1st March

19 (3) July 2006 1st June

19(4) October 2006 1st September

20 (1) January 2007 1st December

Submission Deadlines forT h e Bulletin:

Scientific Sessions of the American Heart Association, Chicago, Illinois, 12-15th November,2006. For further information, please refer to the AHA website: www. americanheart.org

XIX ISHR World Congress in Bologna, Italy 22-26 June 2007. Organizers RobertoFerrari and Luigi Tavazzi. Enquiries: Prof. Roberto Ferrari, Chief of Cardiology, UniversityHospital of Ferrara, Corso Giovecca 203, 44100 Ferrara, Italy. E-mail: [email protected], Website www.ishr-italy2007.org

Travel Reports for The BulletinThe Bulletin editors look forward to publishing travel reports written by BSCRmembers. These can be on any conference, course or laboratory visit of interestto other members and could perhaps contain photographs. If you are planning ontravelling to a cardiovascular-related meeting and would like to write a reportfor the Bulletin, please contact the editors. A bursary of £300 is available to-wards the cost of your visit, and this will be provided on receipt of the report.Bon voyage!

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Sessions devoted to: Interventional Cardiology Development of the Heart New Techniques for Imaging Arrhythmias The Fontan Circulation Debates Difficult Cases

Intended for: Paediatric cardiologists, paediatric cardiac surgeons particularly those in training, paediatricians and cardiologists with an interest in cardiology as seen in the young, paediatric intensivists, and all professionals with

an interest in congenital heart disease including nurses and echocardiographic technicians

Previous participant comments: “Excellent presenters, great illustrations, interesting live transmission from the Operating Room.” “A stimulating academic meeting with cutting edge material.” “Very good course, highly educational. Excellent quality of speakers.”

To register for these courses or to find out about our other events go to

0207 7813 8394 / 829 8692 / 905 2135

[email protected]

Standard Fees: W hole M eeting - £460 (Fee 1 day - £180; 2 days - £360) Doctors in Training: W hole M eeting - £390 (1 day - £140; 2 days £280)

Nurses and Technicians: W hole M eeting – £305 (1 day - £120; 2 days - £220)

Course Organisers: Robert H. Anderson, Andrew Taylor, Jan Marek, Robert Yates and Martin Elliott

This two day course will explore in detail the anatomical basis of selected congenital cardiac malformations, and will show how recent developments in imaging have rationalised the

approach to surgical correction.

The anatomical foundations will first be presented in terms of concepts, and thereafter shown live by means of video demonstration of suitable autopsied specimens. Experts will then show the latest developments in non-invasive imaging,

and recognised innovators in surgical correction will summarise the situation as seen from their perspective, giving insights into the latest operative strategies and, where appropriate, enhancing their presentations with demonstrations of

anatomy as seen in the operating room. Lesions to be discussed: Double Inlet Ventricle, Atrioventricular Valvar Atresia, Hypoplasia of the Left Heart,

Totally Anomalous Pulmonary Venous Connection, Ebstein’s Malformation, Transposition of the Great Arteries

Previous participant comments: “Very good course, it was good to hear experts discussing the different cases. More courses of this nature are needed.”

“An excellent course! It has increased my understanding dramatically”

Culminating in a symposium to celebrate the achievements of Marc de Leval on Saturday 22 April. Course Organisers: John E. Deanfield, Philipp Bonhoeffer, Martin J. Elliott & Robert H. Anderson

Invited Moderators: Gil Wernovsky, Children’s Hospital of Philadelphia &

Jan Quaegebeur, Columbia University, New York

Clinico-Morphological CorrelationsClinico-Morphological CorrelationsClinico-Morphological CorrelationsClinico-Morphological CorrelationsClinico-Morphological Correlations

£295 (£220 Nurses & Technicians)

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PROJECT GRANTS COMMITTEESEPTEMBER 2005DEFERRED APPLICATIONS AWARDEDMr R S Bonser et al, Queen Elizabeth Hospital, Birmingham.“Identification of heart donors using biochemical probes” (2.5years) £273,588

Dr R F Storey, University of Sheffield. “Studies of plateletP2Y12 antagonism: receptor blockade with clopidogrel,inhibition of platelet-mediated inflammatory responses andinteraction with αIIbβ3 receptor antagonists” (2 years) £126,320

Professor N Chaturvedi et al, St Mary’s Hospital, London.“Explanations for the elevated risk of stroke in South Asians”(3 years) £199,940

NEW APPLICATIONS AWARDEDDr A H Baker et al, University of Glasgow. “Evaluation ofsustained efficacy of venous bypass graft gene therapy” (2years) £59,787

Dr H Mellor, University of Bristol. “Control of pro-angiogenicsignals through the regulation of VEGF receptor-2 trafficking”(3 years) £131,520

Dr M Hussain & Professor G Hart, University Of Liverpool.“Mechanisms responsible for the increased functional reservein compensated hypertrophy” (3 years) £90,298

Dr E Kiss-Toth et al, University of Sheffield. “Regulation ofmitogen activated protein kinase signalling by the JIP familyof scaffolding proteins in vascular smooth muscle cells” (3years) £132,302

Prof W A Large & Dr I Greenwood, St George’s, University ofLondon. “Investigation into the expression, modulation andpharmacology of cGMP-dependent chloride channels invascular myocytes” (3 years) £176,815

Professor S E Harding, NHLI, London. “Mechanisms of cardiacdepression by the β2-adrenoceptor” (2 years) £105,639

Dr S J George, Bristol Royal Infirmary. “Regulation of vascularsmooth muscle cell apoptosis by a C-terminal fragment of N-cadherin” (2 years) £76,193

Prof S M Gardiner & Prof M Bennett, Queen’s Medical Centre,Nottingham. “Cardiovascular function in endotoxaemia:influence of changing temporal and regional interactionsbetween adrenomedullin, adenosine and ATP-sensitivepotassium channels” (3 years) £114,440

Dr C Monaco et al, Imperial College London. “Toll-like receptorsignalling in atherosclerosis” (3 years) £97,882

Prof M A Hanson & Dr F W Anthony, University ofSouthampton. “A role for ERα in programming vasculardysfunction in offspring of rat dams fed a low protein dietduring pregnancy” (3 years) £186,413

British Heart Foundation Grants

Professor D C Crossman et al, Northern General Hospital,Sheffield. “Mechanisms regulating risk of myocardial infarctionfollowing infection” (3 years) £129,651

Dr M Burch et al, Great Ormond Street Hospital (UCL). “Therelationship of endothelial damage and dysfunction todevelopment of coronary allograft vasculopathy after cardiactransplant in children”(2 years) £147,510

Professor A J Camm et al, St George’s Hospital Medical School.“Assessment of heart rhythm irregularity and haemodynamicstatus in patients with atrial fibrillation” (2 years) £134,859

Dr J E Hall et al, Cardiff University. “Novel haemostatic assaysto predict bleeding in cardiac surgery” (2 years) £13,808

Dr E Dupont et al, NHLI, London. “Mechanism of actionpotential generation and propagation investigated in agenetically engineered cell model” (3 years) £265,961

Dr P D Lambiase et al, The Heart Hospital. “Electrophysiologicalcharacterisation of arrhythmogenic right ventricularcardiomyopathy in genetically affected probands andasymptomatic relatives using non-contact endocardialmapping” (3 years) £147,121

Dr R J Clarke et al, Radcliffe Infirmary, Oxford. “Genetically-enriched” case-control study of coronary heart disease” (1year) £186,779

Dr C F Lawson & Prof M L Rose, Royal Veterinary College,London. “Role of anti-ICAM-1 antibodies in cardiovasculardisease” (3 years) £99,563

FELLOWSHIPS COMMITTEE OCTOBER2005DEFERRED APPLICATIONS AWARDED

Intermediate Research FellowshipsDr J J Rochford, Addenbrooke’s Hospital, Cambridge. “Earlymolecular events in the control of fat cell development” (3years) £161,804

PhD StudentshipsMr S J Shelton, Queen’s Medical Centre, Nottingham. “A rolefor Serum Response Factor (SRF) in the survival ofcardiomyocytes following hypoxia” (3 years) £74,410Unnamed and Dr CCT Smith, The Hatter Institute, London.“Leptin: a cardioprotective adipocytokine?” (3 years) £79,710

Clinical PhD StudentshipsDr R Sarwar, Imperial College, London. “Genetic determinantsof left ventricular mass” (3 years) £166,344Mr M Saha, St Thomas’ Hospital, London. “Collateralmyocardial blood flow. The relative roles of stenosis severityand circulating endothelial progenitors” (3 years) £206,035

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NEW APPLICATIONS AWARDED

Senior Research FellowshipsDr A Hingorani, University College London. “A researchframework for mendelian randomisation studies ofbiomarkers relevant to cardiovascular disease” (5 years)£559,430Dr P Kohl, University of Oxford. “Cardiac mechano-electric feedback and arrythmias: from pipette to patient”(5 years) £294,761

International FellowshipsDr C Berry, Western Infirmary, Glasgow. “Endothelialrepair: relationships with human coronary atheroma in vivo”(1 year) £51,352Mr M O’Neill, St Mary’s Hospital, London. “Role of nonpulmonary vein sources in maintenance of atrial fibrillation”(1 year) £43,255

Intermediate Research FellowshipsDr S Jiang, Guy’s Hospital, London. “Preclinical study ofCD4+CD25+ regulatory T cells with indirect allospecificityas cell therapy to induce donor-specific cardiactransplantation tolerance” (3 years) £164,231Dr N Ahmed, University of Essex. “Hotspot glycation ofapolipoprotein B100 by dicarbonyls at LDL receptorrecongition domains - importance in dyslipidaemia andatherosclerosis in diabetes” (3 years) £133,714Dr S Padmanabhan, University of Glasgow. “Hypertensionpharmacogenetics - discovering genetic determinants ofblood pressure response” (3 years) £256,205

Junior Research FellowshipsMr J Watt, University of Strathclyde. “Coronary stentdeployment, oxidative stress, endothelial regeneration andrisk of thrombosis” (2 years) £89,376Dr P Heck, Addenbrooke’s Hospital, Cambridge. “Theeffects of hyperinsulinaemia and hyperglycaemia onmyocardial performance in patients with coronary arterydisease” (2 years) £97,836Dr D Sharkey, University of Nottingham. “Programmedto fat dysfunction - the early origins of cardiovascular andmetabolic disease?” (2 years) £96,578

4 Year PhD Studentships (3 candidates each)Prof J Mullins, University of Edinburgh (candidates: MissCaroline Tabor; Ms Agnieszka Kozak; Mr StylianosBournazos) (4 years) £293,337Prof J D Pearson, King’s College London (candidates: MissSara Alom Ruiz; Mr Andrew Hall; Miss Negin Sarafraz-Shekary) (4 years) £311,286Dr D Greaves, John Radcliffe Hospital, Oxford (candidates:Mr Tom Collins; Miss Jenna Cash; Miss Anna Michell) (4years) £314,166

Clinical PhD StudentshipsDr S Hamdulay, Hammersmith Hospital, London. “Statinsand rapamycin - therapeutic synergy in vascularcytoprotection” (3 years) £174,309Dr V Bills, St Michael’s Hospital, Bristol. “Vascularpermeability in pre-eclampsia” (3 years) £134,956Dr R Ray, King’s College London. “The role of the NADPHoxidase isoform NOX4 in endothelial cells in vivo” (3 years)£164,357Dr Z Astroulakis, King’s College London. “Endothelialprogenitor cell reserve and response to exercise and cardiacrehabilitation” (3 years) £183,329

PhD StudentshipsMs K E Skene, Robert Gordon University, Aberdeen.“Studies on the role of the endocannabinoid anandamideas a possible modulator of events during neointimalformation” (3 years) £76,901Mrs S Shakya Shrestha, University of Cambridge. “Aprospective population study of dietary and plasmacarotenoids and coronary heart disease” (3 years) £84,949Unnamed and Dr D Lang, Cardiff University. “Mechanismsof vascular dysfunction in rheumatoid arthritis” (3 years)£85,971Unnamed and Dr P E James, Cardiff University. “Nitriteuptake and metabolism in human erythrocytes - a sourceof vascular nitric oxide?” (3 years) £78,454Mr J A Hansell, University of Cambridge. “Developmentalprogramming of cardiovascular disease by hypoxia andoxidative stress” (3 years) £84,646Unnamed and Prof A H Baker, Western Infirmary, Glasgow.“Design and evaluation of in vivo targeted anti- oxidantpeptides” (3 years) £78,883Miss I Campesi, Bristol Royal Infirmary. “Effect of nervegrowth factor (NGF) on diabetes-induced apoptosis ofcardiomyocytes and endothelial cells and intra-myocardialNGF gene transfer to combat diabetic cardiomyopathy inmice” (3 years) £78,173Unnamed and Dr S J Harper, University Of Bristol.“Capillary permeability and ultrastructure inmicroalbuminuria” (3 years) £78,881Miss C Major, University of Nottingham. “The role ofstearoyl coenzyme A desaturase in regulating lipid andlipoprotein metabolism” (3 years) £78,643Ms A Tatham, University of Oxford. “Identifying keyregulators of tetrahydobiopterin synthesis” (3 years)£88,653Unnamed and Dr P I Aaronson, Guy’s Hospital, London.“The role of small heat shock proteins in p38 MAP kinase-mediated suppression of nitric oxide-inducedvasorelaxation” (3 years) £84,073Mr M Black, John Moores University, Liverpool. “Theeffects of exercise training on endothelial and smoothmuscle function in older men and women” (3 years)£72,907

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Overseas Visiting FellowshipDr I Lornezen-Schmidt, From University of California,USA to University of Oxford. “Subcellular signalingmechanisms in cardiac mechanoelectric feedback” (2years) £65,394

Travelling FellowshipsDr M L Penichet, From University of California, USA toUniversity of Surrey. “The use of antibody-cytokine fusionproteins to reprogram the immune system inatherosclerosis” (10 days) £1,350Mr H S Leong, From St Paul’s Hospital, Vancouver, Canadato Harefield Hospital, Middx. “The role of polymericvitronectin and endothelial vimentin in the generation ofvimentin antibodies and transplant graft vasculopathy” (3months) £3,000

CHAIRS AND PROGRAMME GRANTSCOMMITTEE NOVEMBER 2005

Programme GrantsProf RC Trembath and Dr NW Morrell, King’s College London.“The molecular genetics of pulmonary arterial hypertension”2 years, 5 months (renewal: years 6-8) £476,011Prof PJ Scambler, University College London. “Developmentalgenetics of DiGeorge (22q11 deletion) syndrome: investigationof pathways controlled by the transcription factor Tbx1” 5years (renewal: years 6-10) £1,005,552Prof S Humphries and Prof P Talmud, University CollegeLondon. “Functional genetic variants and DNA-based testsfor coronary heart disease risk” 3 years (renewal: years 21-25)£675,873Dr AW Poole and Dr SJ Mundell, University of Bristol “Roleof PKC isoforms in platelet function” 5 years £836,191

Wellcome Trust GrantsSeptember to October 2005

Programme GrantDr Andrew A Grace, Department ofBiochemistry, Main Building, University ofCambridge. “Integrative Physiology of CardiacArrhythmias” 36 months £573,072

Equipment GrantDr Christopher M H Newman, CardiovascularResearch Group, Clinical Science Centre,Northern General Hospital, University ofSheffield. “Mulitphoton FluorescenceMicroscopy facilities for the in vitro and in vivoinvestigation of fundamental processes invascular biology” 60 months £597,287

Research Training FellowshipsDr Chee Wan Lee, Department of CardiovascularMedicine, John Radcliffe Hospital, Universityof Oxford. "Gene transfer to assess neuralcontrol of cardiac excitability followingmyocardial infarction" 36 months £224,330

Dr O J Rider, Department of CardiovascularMedicine, John Radcliffe Hospital, Universityof Oxford. "Effects of uncomplicated obesity onthe cardiovascular system" 36 months £213,186

HCPC PhD FellowshipDr J J Miranda-Montero, Department ofEpidemiology and Pop Health, EpidemiologyUnit, London School of Hygiene and TropicalMedicine, London. “The effect on cardiovascularrisk factors of migration from rural to urbanareas in Lima, Peru” 36 months £107,962

Project GrantProfessor Bonnie A Wallace, Department ofCrystallography, Birkbeck College, London."Structure, function and drug interactions involtage-gated sodium channels" 36 months£289,207

Articles for The BulletinWould you like to write a Review or LaboratoryProfile for the BSCR Bulletin? These articlesprovide an excellent opportunity to let BSCR

members know about your research activities andalso provide an insight into your research field.

We are keen to hear from anyone in cardiovascularresearch who would be willing to write for TheBulletin. If you are interested, please contact the

Bulletin editors with your ideas:

Helen ([email protected]) or Nicola([email protected])

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BSCR Spring Meeting 2006Cardiovascular Genomics

Dates: Monday 27th and Tuesday 28th March, 2006

Venue: Hinxton Hall Conference Centre, Wellcome Trust Sanger Institute, Cambridge.

Organisers: Dr Andrew Grace, Dr Jane Rogers and Dr Willem Ouwehand.

Objectives: The principal objective is to present the current state-of-play in applied cardiovascular genetics.We also want to look forward and explore how high-throughput technologies can increase the pace of discovery.

Programme: The programme will consist of state-of-the-art presentations by leaders in the field. Part of themeeting will be devoted to oral presentation of selected abstracts, and poster presentations. Prizes will beawarded for the best oral and best poster presentations given by young investigators.

Speakers will include: David Clayton (Cambridge), Panagiotis Deloukas (Wellcome Trust Sanger Institute),Bruce Furie (Boston), Andrew Grace (Cambridge), Aroon Hingorani (London), James Metcalfe (Cambridge),Calum McCrae (Boston), Dan Roden (Vanderbilt), Nilesh Samani (Leicester), Eric Schulze-Bahr (Münster),Hugh Watkins (Oxford), Nick Watkins (Cambridge).

Travel & Accommodation: Details can be found at: http://www.hinxton.wellcome.ac.uk/conference/Conferance.htm.Accommodation will be available on a first come basis at the Wellcome Trust Conference Centre Facility.

Communications: Part of the meeting will be devoted to oral presentation of selected abstracts and posters.There are two prizes of £250 each: the Clinical Science Young Investigator Award and the BSCR Young InvestigatorAward.

Registration (excluding accommodation): Free for BSCR members, £40 for non-members.

Bursaries: The Society will consider awarding travel grants of up to £150 to bona fide students.

The programme, abstract pro-forma, meeting registration / accommodation forms and forms for applicationfor student bursaries are available for downloading from the BSCR website (www.bscr.org)

Deadline for submission of abstracts, registration and application for student bursaries: 3rd February,2006

Any further enquiries to: Dr Andrew Grace, Section of Cardiovascular Biology, Department ofBiochemistry, Tennis Court Road, Cambridge CB2 1QW. Please contact Sophie Hawkins([email protected]).

Or: Professor Barbara McDermott, BSCR Secretary, Therapeutics & Pharmacology, Queen’s UniversityBelfast, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL; Tel 02890-972242; Fax 02890-438346; [email protected]

january 2006 - bscr · 2014. 11. 17. · dr michael j. curtis cardiovascular research rayne...

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