Imperial College London
Alternate

Dr Neil Dufton

Faculty of Medicine, National Heart & Lung Institute

Honorary Research Associate
 
 
 
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Contact

 

+44 (0)20 7594 2728n.dufton

 
 
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Location

 

525W5ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Dowsett:2015:10.1161/CIRCULATIONAHA.114.015064,
author = {Dowsett, L and Piper, S and Slaviero, A and Dufton, N and Wang, Z and Boruc, O and Delahaye, M and Colman, L and Kalk, E and Tomlinson, J and Birdsey, G and Randi, AM and Leiper, J},
doi = {10.1161/CIRCULATIONAHA.114.015064},
journal = {Circulation},
pages = {2217--2225},
title = {Endothelial dimethylarginine dimethylaminohydrolase 1 Is an important regulator of angiogenesis but does not regulate vascular reactivity or hemodynamic homeostasis},
url = {http://dx.doi.org/10.1161/CIRCULATIONAHA.114.015064},
volume = {131},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Background—Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthesis and a risk factor for cardiovascular disease. Dimethylarginine dimethylaminohydrolase (DDAH) enzymes are responsible for ADMA breakdown. It has been reported that endothelial DDAH1 accounts for the majority of ADMA metabolism. However, we and others have shown strong DDAH1 expression in a range of nonendothelial cell types, suggesting that the endothelium is not the only site of metabolism. We have developed a new endothelium-specific DDAH1 knockout mouse (DDAH1En−/−) to investigate the significance of endothelial ADMA in cardiovascular homeostasis.Methods and Results—DDAH1 deletion in the DDAH1En−/− mouse was mediated by Tie-2 driven Cre expression. DDAH1 deletion was confirmed through immunocytochemistry, whereas Western blotting showed that DDAH1 remained in the kidney and liver, confirming expression in nonendothelial cells. Plasma ADMA was unchanged in DDAH1En−/− mice, and cultured aortas released amounts of ADMA to similar to controls. Consistent with these observations, vasoreactivity ex vivo and hemodynamics in vivo were unaltered in DDAH1En−/− mice. In contrast, we observed significantly impaired angiogenic responses both ex vivo and in vivo.Conclusions—We demonstrate that endothelial DDAH1 is not a critical determinant of plasma ADMA, vascular reactivity, or hemodynamic homeostasis. DDAH1 is widely expressed in a range of vascular and nonvascular cell types; therefore, the additive effect of DDAH1 expression in multiple organ systems determines plasma ADMA concentrations. Endothelial deletion of DDAH1 profoundly impairs the angiogenic capacity of endothelial cells, indicating that intracellular ADMA is a critical determinant of endothelial cell response.
AU  - Dowsett,L
AU  - Piper,S
AU  - Slaviero,A
AU  - Dufton,N
AU  - Wang,Z
AU  - Boruc,O
AU  - Delahaye,M
AU  - Colman,L
AU  - Kalk,E
AU  - Tomlinson,J
AU  - Birdsey,G
AU  - Randi,AM
AU  - Leiper,J
DO  - 10.1161/CIRCULATIONAHA.114.015064
EP  - 2225
PY  - 2015///
SN  - 0009-7322
SP  - 2217
TI  - Endothelial dimethylarginine dimethylaminohydrolase 1 Is an important regulator of angiogenesis but does not regulate vascular reactivity or hemodynamic homeostasis
T2  - Circulation
UR  - http://dx.doi.org/10.1161/CIRCULATIONAHA.114.015064
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000360528400008&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.114.015064
VL  - 131
ER  -
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