Title: Nitric Oxide Signalling
Funder: Medical Research Council

Abstract: 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.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR