European Heart Journal Advance Access originally published online on March 18, 2009
European Heart Journal 2009 30(9):1142-1150; doi:10.1093/eurheartj/ehp061
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: implications for endothelial function in human atherosclerosis
1 Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK
2 1st Cardiology Department, Athens University Medical School, Athens, Greece
Received 20 May 2008; revised 21 January 2009; accepted 30 January 2009; online publish-ahead-of-print 18 March 2009.
* Corresponding author. Tel: +44 186 585 1085, Fax: +44 186 522 2077, Email: keith.channon{at}cardiov.ox.ac.uk (K.M.C.) or antoniad{at}well.ox.ac.uk (C.A.)
Background: Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is considered to be a risk factor for atherosclerosis. However, the mechanisms relating ADMA with vascular function have been evaluated in vitro and in animal models, but its effect in human vasculature is unclear.
Aims: We examined the impact of serum ADMA on endothelial nitric oxide (NO) bioavailability and vascular superoxide radical (O2-) production in patients with advanced atherosclerosis.
Methods and results: Paired samples of saphenous veins (SVs) and internal mammary arteries (IMAs) were collected from 201 patients undergoing coronary bypass surgery, and serum ADMA was measured pre-operatively. The vasomotor responses of SV segments to acetylcholine (ACh) and bradykinin (Bk) were evaluated ex vivo. Vascular O2- was measured in paired SV and IMA by lucigenin-enhanced chemiluminescence. The L-NAME-inhibitable as well as the NADPH-stimulated vascular O2- generation was also determined by chemiluminescence. High serum ADMA levels were associated with decreased vasorelaxation of SV to ACh (P < 0.05) and Bk (P < 0.05). Similarly, high serum ADMA was associated with higher total O2- production in both SVs and IMAs (P < 0.05) and greater L-NAME-inhibitable vascular O2- (P < 0.05). However, serum ADMA was not associated with NADPH-stimulated vascular O2-. In multivariable linear regression, serum ADMA was independently associated with vascular O2- in both SVs [β (SE): 0.987 (0.412), P = 0.019] and IMAs [β (SE): 1.905 (0.541), P = 0.001]. Asymmetrical dimethylarginine was also independently associated with maximum vasorelaxation in response to both ACh [β (SE): 14.252 (3.976), P = 0.001] and Bk [β (SE): 9.564 (3.762), P = 0.013].
Conclusion: This is the first study that demonstrates an association between ADMA and important measures of vascular function, such as vascular O2- production and NO bioavailability directly in human vessels. Although serum ADMA has no effect on NADPH-stimulated superoxide in intact vessels, it is associated with greater eNOS uncoupling in the human vascular endothelium of patients with coronary artery disease.
Key Words: Endothelial nitric oxide synthase • Asymmetrical dimethylarginine • Nitric oxide • Superoxide