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Professor Giovanni E Mann BSc MSc PhD

Professor of Vascular Physiology

Mann,GiovanniCardiovascular Division
Franklin-Wilkins Building (Rm 3.01)
King's College London
London SE1 9NH
Tel/Fax: +44 (0)20 7848 4306
Email: giovanni.mann@kcl.ac.uk

Biography

Professor Mann obtained his BSc in Zoology (1973) from George Washington University, Washington D.C. USA and MSc (1974) and PhD in Physiology (1978) from University College London. He was then appointed to a 4-year postdoctoral research fellowship at Queen Elizabeth College and then a Lectureship in Physiology (1981), Readership in Physiology (1992) and as Professor of Vascular Physiology at King's College London in 1997.

He has served as Chairman and Deputy Chairman of the Executive Committee of The Physiological Society, President of the European Pancreatic Society, Council Member of the Physiological Society, Society for Free Radical Research-Europe, European Society for Microcirculation, Microcirculatory Society USA International Liaison Committee and was recently elected President of the British Microcirculation Society. Professor Mann is an Associate Editor for Free Radical Biology and Medicine, Editor for Free Radical Research, Editorial Advisor for the Biochemical Journal, and serves on the International Advisory Board of Acta Physiologica Sinica. He is currently a member of the Basic Science Panel of Heart Research UK, Board of External Referees for the Biotechnology and Biological Sciences Research Council and College of Experts for the Medical Research Council - Physiological Systems & Clinical Sciences. He has previously served on grant panels of the British Heart Foundation and Guy's Charitable Foundation. At KCL he is closely involved in postgraduate studies and as Head of Graduate Research in the School of Biomedical & Health Sciences is actively involved in establishing research and postgraduate exchange links with universities in China, hosting K.C. Wong/China Scholarship Council PhD Scholars.

Research interests

Professor Mann's Vascular Biology Group is investigating the signalling cascades involved the transcriptional activation of antioxidant defence genes in endothelial and smooth muscle cells in oxidative stress. We are particularly interested in vascular dysfunction induced by oxidative stress in diseases such as atherosclerosis, pre-eclampsia, chronic renal failure and diabetes. Our research focuses on the L-arginine-nitric oxide (NO) and heme oxygenase-carbon monoxide (CO) signalling pathways, and the role of the redox sensitive transcription factor Nrf2 as a major regulator of antioxidant responsive element (ARE) mediated gene expression.

Mann1250wPolyphenol induced transcriptional activation of redox sensitive genes.
Isoflavones, estrogens and other polyphenols activate intracellular kinase cascades, leading to increased NO, ROS or peroxynitrite levels. Modification of cysteine residues on Keap-1 results in dissociation and nuclear translocation of the redox sensitive transcription factor Nrf2, which in turn binds to an antioxidant response element (ARE) or electrophile response element (EpRE) in the promoter region of target genes (e.g. phase II and antioxidant enzymes NQO1, HO-1, GPx) whilst estrogen receptors bind to estrogen response elements (ERE) to enhance eNOS expression.

Antioxidant gene expression in atherosclerosis
In collaboration with Dr RCM Siow and Prof T Ishii (Univ. Tsukuba, Japan), we have shown that oxidized LDL inhibits NO and PGI2 production in human endothelial cells whilst enhancing expression of the antioxidant stress proteins in human smooth muscle cells. Pretreatment of cells with vitamin C markedly attenuated oxidized LDL induced adaptive increases in heme oxygenase-1 (HO-1) expression, increases in transport of L-cystine (rate-limiting precursor for GSH synthesis) and intracellular GSH, and prevented smooth muscle cell apoptosis (Siow et al., 1999). Our studies in wild type and knockout mice (Ishii et al., 2004) established that the redox sensitive transcription Nrf2 coordinates the induction of the antioxidant stress proteins HO-1 and Prx 1 (H2O2 scavenger) in murine macrophages and aortic smooth muscle cells in response to oxidized lipoproteins. This study provided the first evidence that Nrf2, in addition to coordinating cellular defences against reactive oxygen species (ROS), acted in concert with PPARg to regulate expression of the scavenger receptor CD36. Further information is available in recently invited review articles (Mann et al., 2007; Siow et al., 2007).

Mann2425wDysfunction of human endothelial and smooth muscle cells in pre-eclampsia
Pre-eclampsia is a leading cause of fetal and maternal mortality. In collaboration with Dr R Jacob and Prof L Poston, we have shown that pre-eclampsia is associated with abornmalities in Ca2+ regulation and NO production in fetal endothelial cells (Steinert et al., 2002). We subsequently reported the first evidence that arachidonic acid-stimulated Ca2+ signalling is modulated differently in fetal smooth muscle cells in pre-eclampsia and that preferential metabolism of arachidonic acid via monooxygenase could lead to increased fetal vascular tone in pre-eclampsia (Steinert et al., 2003). In collaboration with Prof Richard Naftalin and Dr Iram Afzal-Ahmed, we reported the first evidence that decreased G6PD activity in pre-eclampsia is associated with impaired fetal endothelial function and redox regulation, potentially accounting for the inability of antioxidant vitamin C/E supplementation to counteract oxidative stress in pre-eclampsia (Afzal-Ahmed et al., 2007). As these phenotypic changes in endothelial and smooth muscle function persist during culture in vitro, our findings are of relevance to the fetal programming of cardiovascular disease.

Dysfunction of the L-arginine-NO signalling pathway in chronic renal and heart failure
Endothelial dysfunction is widely accepted as an important mechanism contributing to altered vascular resistance in patients with chronic renal and heart failure. Increased NO synthesis in patients with renal or heart failure appears to be a failing counter-regulatory mechanism. In collaboration with Dr AC Mendes Ribeiro (UERJ, Brazil) and Professor Clive Ellory (Univ. Oxford), we are investigating the mechanisms underlying our observation that chronic renal and heart failure are associated with decreased plasma arginine levels (but increased L-NMMA levels) and increased rates of L-arginine transport via system y+ (CAT-1) in human red blood cells and peripheral blood mononuclear cells. Our studies in human platelets provided the first evidence that uraemia is associated with an up-regulation of the high-affinity amino acid transport system y+L, accounting for the paradox of increased NO production by uraemic platelets under conditions of decreased plasma L-arginine and elevated L-NMMA concentrations (see da Silva et al., 2005). We recently reported that hypertension is associated with an inhibition of L-arginine transport via system y+L in both humans and animals, with reduced availability of L-arginine limiting NO biosynthesis and further information is available in invited review articles (Mendes-Ribeiro et al., 2001; Brunini et al., 2006).

Acute and genomic vascular actions of estrogens, phytoestrogens and environmental pollutants
Epidemiological evidence suggests that estrogens are cardioprotective, with pre-menopausal women having a lower incidence of coronary heart disease (CHD) compared to age-matched men. The incidence of CHD increases significantly after menopause, with loss of cardiovascular protection attributed to estrogen deficiency. As recent clinical trials (HERS and WHI) highlighted the lack of benefit of combined estrogen plus progestin therapy for CHD, the search for alternative therapy has precipitated studies on the potential benefits of selective estrogen receptor modulators (see reviews Mann et al., 2007; Siow et al., 2007). We are currently studying the acute actions of phytoestrogens on the signalling cascades involved in endothelial NO biosynthesis and the genomic actions in wildtype and ERα and ERß knockout mice.

Classical actions of estrogens are mediated via transcriptional activation of estrogen responsive genes involving intracellular estrogen receptors (ERs). Once estrogen binds to ERs, allosteric changes in the receptor-ligand complex allow for the dissociation of chaperone proteins and homo- or heterodimerisation of ERs. There is an ongoing scientific debate concerning the potential threat of environmental pollutants to animal and human health. Persistent estrogenic pollutants, such as chlorinated insecticides and the alkylphenolic detergents octylphenol and nonylphenol, have been reported to modulate sexual differentiation by interacting with nuclear steroid receptors. In this context, we reported that o.p’DDT and octylphenol mimic acute vasodilator actions of 17ß-estradiol by inhibiting Ca2+ influx via L-type calcium channels in vascular smooth muscle cells (Ruehlmann et al., 1998), and subsequently provided evidence for a direct interaction of estrogen with the ß-subunit of the Maxi-K channel in vascular smooth muscle (Valverde et al., 1999).

Localisation of estrogen receptor α and β immunoreactivity in human fetal endothelial cells.
A, limited overlapping immunoreactive loci for estrogen receptors α and β (red dots represent ERα-IR, green dots ERβ-IR). B, white rectangle in A is shown at higher magnification. C, at the EM level, ERβ-IR was revealed by silver-intensified gold particles in the cell membrane (white arrows). D, black rectangle in C is shown at higher magnification, note the plasmalemmal localisation of ERβ immunoreactivity.

Our recent studies in human fetal endothelial cells established that nutritionally relevant plasma concentrations of equol (and other soy isoflavones) rapidly stimulate phosphorylation of ERK1/2 and PI(3)-kinase/Akt, leading to the activation of NOS and increased NO production at resting cytosolic Ca2+ levels (Joy et al., 2006). Identification of the non-genomic mechanisms by which equol mediates vascular relaxation provides a basis for evaluating potential benefits of equol in the treatment of postmenopausal women and patients at risk of cardiovascular disease.

We receive external research funding from the British Heart Foundation, Heart Research Fund UK, Wellcome Trust, Guy’s & St. Thomas’ Charitable Foundation and European Foundation for the Study of Diabetes/Servier. Techniques are up-and-running for membrane transport studies, in vitro organ perfusion and isometric tension recordings from arterial vessels, myography, radioimmunoassays, fluorescence [Ca2+]i measurements and molecular biology. Moreover, we have established breeding colonies of estrogen receptor and Nrf2 knockout mice, providing unique models to explore altered gene expression and nitric oxide production under conditions of oxidative stress associated with vascular diseases.

Group members

Postdoctoral Fellows

  • Dr Sarah Chapple
  • Dr Eiji Warabi
  • Dr Alessio Alfieri

PhD Students

  • Mr Salil Srivistava (BHF 4 year Studentship) 
  • Mr Thomas Keeley (BHF Non-clinical Studentship) 
  • Ms Li Li (King's China scholarship) 
  • Ms Bijal Patel (BHF Non-clinical studentship) 

Collaborators

  • Dr Phil Aaronson (KCL)
  • Prof Clive Ellory (Univ. Oxford)
  • Dr Albert Ferro (KCL)
  • Dr Paul Fraser (KCL)
  • Dr Luigi Gnudi (KCL)
  • Prof Tetsuro Ishii (Univ.Tsukuba)
  • Dr Ron Jacob (KCL)
  • Dr David Leake (Univ. Reading)
  • Dr AC Mendes-Ribeiro (UERJ, Brazil)
  • Prof Richard Naftalin (KCL)
  • Prof Jeremy Pearson (KCL)
  • Prof Guiseppe Poli (Univ. Torino)
  • Prof Lucilla Poston (KCL)
  • Dr Richard Siow (KCL)
  • Prof Jose Viña (Univ. Valencia)
  • Prof Jeremy Ward (KCL)
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