Nitric Oxide Signalling

Lead Research Organisation: MRC Clinical Sciences Centre

Abstract

Nitric oxide is an important regulator of blood vessel function that modulates vascular relaxation and thereby contributes to the maintenance of normal blood pressure. Reduction in vascular nitric oxide production causes cardiovascular diseases including hypertension, athero-sclerosis and heart failure in experimental animals. In patients with cardiovascular disease reduced nitric oxide production has been observed. We have identified a novel pathway that has the potential to regulate nitric oxide synthesis. Thus, naturally occurring modified forms of the amino acid arginine (ADMA) block nitric oxide synthesis. In this programme of work we plan to 1) Elucidate the role of ADMA in the regulation of cardiovascular function during health and disease, 2) Determine the role of the genes that regulate ADMA levels in the regulation of cardiovascular function in healthy humans and patients with cardiovascular disease, 3) Explore the therapeutic potential of altering the levels of ADMA in cardiovascular disease states, 4) Investigate the unexpected finding that ADMA plays a critical role during embryonic development. At the end of this programme we will have a clear understanding of role of ADMA in the regulation of cardiovascular function in humans and the potential to develop new medicines based upon manipulation of the concentration of these molecules.

Technical Summary

Asymmetric dimethylarginine was first described by Vallance et al. in 1992 as an endogenous inhibitor of nitric oxide synthases (NOS) that accumulates in patients with renal failure. Since then plasma ADMA has been shown to predict cardiovascular events and overall mortality in patients with end stage renal failure, and plasma levels appear to be elevated in a wide range of human disease states including hypertension, atherosclerosis, preeclampsia and heart failure. In humans the major route of clearance of ADMA is metabolism catalysed by two isoforms of the enzyme dimethylarginine dimethylamino-hydrolase (DDAH). In experimental animals, genetic or pharmacological depletion of DDAH activity leads to increases in ADMA concentrations, inhibition of cardiovascular nitric oxide (NO) generation and hypertension. These data suggest that DDAH, acting via ADMA, is a significant regulator of NO production in vivo and suggest that genetic or environmental factors that modulate DDAH activity in humans might have a significant impact on cardiovascular function and disease progression. This programme is focussed on ADMA and its metabolic pathways across a range of cardiovascular physiology and pathophysiology.|Endogenously produced ADMA can exert significant effects on cardiovascular function under normal physiological conditions and that DDAH is an important regulator of ADMA levels in vivo. However, whilst global over expression/ deletion of DDAH genes and inhibition of DDAH activity in experimental animals have provided the first evidence for a causal role for the DDAH/ADMA pathway in the regulation of cardiovascular nitric oxide signalling our understanding of the mechanisms that dynamically regulate DDAH expression and the identity of key cardiovascular cell types in which DDAH and ADMA exert significant effects during both physiological and pathophysiological situations remains limited. Moreover it is unclear how the observations from experimental animals translate to the situation in man. Finally, a deeper understanding of the functions of DDAH may provide novel therapeutic opportunities, particularly where excessive nitric oxide production contributes to pathology.|We have generated reagents and a depth of expertise in this field that is recognised as unique. Resources include DDAH1 and 2 global, conditional and inducible knockout and transgenic mice, potent inhibitors of DDAH, DDAH crystal structures and identified single nucleotide polymorphisms in human DDAH genes that modulate expression levels. In this programme of work we plan to utilise these reagents and expertise to understand 1) the mechanisms of action of DDAH and ADMA in the regulation of cardiovascular function in health and disease 2) the contribution of genetic variation in DDAH to the progression of disease in human populations 3) the therapeutic potential of small molecule modulators of DDAH activity and 4) role of DDAH1 during embryonic development. This programme is wide ranging spanning the fields of molecular, structural and chemical biology, cardiovascular physiology, human genetics and developmental biology. Research in our group is currently funded by a BHF programme grant, a Wellcome Trust translational award and a European Commission FP6 award. The additional resources requested from the MRC will allow us to develop a fully integrated programme with the potential to translate our basic research findings into new therapeutics for the treatment of human disease.

Publications


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Breckenridge RA (2010) A role for Dimethylarginine Dimethylaminohydrolase 1 (DDAH1) in mammalian development. in The International journal of developmental biology
Bulau P (2007) Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA. in American journal of physiology. Lung cellular and molecular physiology
Caplin B (2012) Endogenous nitric oxide synthase inhibitors in the biology of disease: markers, mediators, and regulators? in Arteriosclerosis, thrombosis, and vascular biology
 
Description BHF PhD Studentship
Amount £75,300 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2012 
End 09/2015
 
Description BHF PhD Studentship
Amount £85,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2011 
End 04/2014
 
Description BHF Programme Grant
Amount £1,302,907 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start  
 
Description BHF Project Grant
Amount £94,114 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start  
 
Description British Heart Foundation Project Grant
Amount £183,010 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 09/2009 
End 09/2012
 
Description British Heart Foundation Project Grant
Amount £254,086 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 09/2009 
End 09/2012
 
Description ESRC Platform Grant
Amount £760,000 (GBP)
Organisation Economic and Social Research Council (ESRC) 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start  
 
Description European Commission FP6
Amount £285,000 (GBP)
Organisation Sixth Framework Programme (FP6) 
Sector Public
Country European Union (EU)
Start  
 
Description European Commission FP6 Network of Exellence
Amount £120,000 (GBP)
Organisation Sixth Framework Programme (FP6) 
Sector Public
Country European Union (EU)
Start  
 
Description MRC Intramural Research Programme Funding
Amount £2,800,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 05/2009 
End 05/2014
 
Description MRC Technology Development Gap.Fund.
Amount £108,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2012 
End 03/2013
 
Description Wellcome Trust Equipment Grant
Amount £358,750 (GBP)
Organisation The Wellcome Trust Ltd 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start  
 
Description Wellcome Trust Project Grant
Amount £236,395 (GBP)
Organisation The Wellcome Trust Ltd 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start  
 
Description Wellcome Trust Seeding Drug Discover Initiative
Amount £4,200,000 (GBP)
Organisation The Wellcome Trust Ltd 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start  
 
Description BHF Project Grant 
Organisation University College London (UCL)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Co applicants
Collaborator Contribution Co-applicant and grant
Impact N/A
Start Year 2009
 
Description BHF Studentship 
Organisation Faculty of Medicine
Department Department of Medicine
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Co-applicants on grant
Collaborator Contribution Co-applicants on grant
Impact N/A
Start Year 2011
 
Title Assay for measuring asymetric methylarginine in a biological sample 
Description Assay for measuring asymetric methylarginine in a biological sample 
IP Reference US2009053741 
Protection Patent application published
Year Protection Granted 2006
Licensed Yes
Impact n/a
 
Title Assay for measuring asymetric methylarginine in a biological sample 
Description Assay for measuring asymetric methylarginine in a biological sample 
IP Reference US2009053741 
Protection Patent granted
Year Protection Granted 2009
Licensed Yes
Impact n/a
 
Title Dimethylarginine Dimethylaminohydrolases 
Description Dimethylarginine Dimethylaminohydrolases 
IP Reference US20040966039 
Protection Patent application published
Year Protection Granted
Licensed Yes
Impact n/a
 
Title Guanidine derivatives as inhibitors of DDAH 
Description Guanidine derivatives as inhibitors of DDAH 
IP Reference US20050719208 
Protection Patent application published
Year Protection Granted
Licensed Yes
Impact n/a
 
Title Screen Method 
Description Screen Method 
IP Reference WO0044888 
Protection Patent application published
Year Protection Granted
Licensed Yes
Impact n/a
 
Description 3rd International Symposium on ADMA Research, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Member of the organising committee

n/a
Year(s) Of Engagement Activity 2006
 
Description 3rd International Workshop on Cardiovascular Biology, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Member of the organising committee.

n/a
Year(s) Of Engagement Activity 2008
 
Description 4th International Symposium on ADMA Research, Bregenz, Austria 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Member of the organising committee

n/a
Year(s) Of Engagement Activity 2008
 
Description 5th International Symposium on ADMA, Chicago, USA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Member of the organising committee

n/a
Year(s) Of Engagement Activity 2010
 
Description 6th International Symposium on ADMA Research, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Member of the organising committee

n/a
Year(s) Of Engagement Activity 2012
 
Description Annual World Congress on the Insulin Resistance Syndrome 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact n/a
Year(s) Of Engagement Activity 2006
 
Description Frontiers in Vascular Medicine, Melbourne, Australia 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact n/a
Year(s) Of Engagement Activity 2007
 
Description Inflammation Research Association Meeting: 25 Years of Nitric Oxide Research, Boston, US 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact n/a
Year(s) Of Engagement Activity Pre-2006
 
Description Japanese Renal Association Meeting, Shizoka, Japan 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact n/a
Year(s) Of Engagement Activity 2009
 
Description Lecturer on Drug Design and Development Course 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Lecturer at UCL, PHAR3006. 2002 to date.

n/a
Year(s) Of Engagement Activity Pre-2006
 
Description Lecturer on Molecular Medicine MSc Course 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Imperial College London, 2009 to date

n/a
Year(s) Of Engagement Activity 2009
 
Description LifeSciences, Glasgow 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact n/a
Year(s) Of Engagement Activity 2007
 
Description MDC/CSC Retreat 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Presented 20 minute talk followed by 10 minute discussion.

N/A
Year(s) Of Engagement Activity 2011
 
Description Organiser of The Heart and Circulation Course 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Organiser of the third year module for non-clinical and clinical undergraduates. (University College London PHOL 3002. 2006-2009)

n/a
Year(s) Of Engagement Activity 2006
 
Description World Conference of Nephrology, Milan, Italy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact n/a
Year(s) Of Engagement Activity 2009
 
Description World Congress of Nephrology, Kyoto, Japan 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact n/a
Year(s) Of Engagement Activity 2010