Nebivolol reduces asymmetric dimethylarginine in endothelial cells by increasing dimethylarginine dimethylaminohydrolase 2 (DDAH2) expression and activity.
Asymmetric dimethylarginine (ADMA) has been reported to affect the synthesis of nitric oxide (NO) in endothelial cells by inhibiting endothelial NO synthase (eNOS) activity and to cause endothelial dysfunction in humans. This study was conducted in human umbilical vein endothelial cells (HUVECs) to evaluate the effect of nebivolol, a selective beta1-adrenergic receptor antagonist, on ADMA concentration and on dimethylarginine dimethylaminohydrolase (DDAH2), the enzyme that regulates ADMA catabolism. Nebivolol dose-dependently decreased ADMA/symmetric dimethylarginine (SDMA) ratio (p from <0.01 to <0.001). This was parallelled by a dose-dependent increase in DDAH2 mRNA (p from <0.01 to <0.001) and protein expression (p from <0.01 to <0.001) and activity (p from <0.01 to <0.001). The small interference RNA (siRNA)-mediated knockdown of DDAH2 abolished the modification of DDAH2 expression (p<0.001) and ADMA/SDMA ratio (p<0.001) induced by nebivolol. In conclusion, the results of this study demonstrate that nebivolol reduces ADMA concentration by increasing DDAH2 expression and activity. Our in vitro findings describe a novel vascular effect of nebivolol and clearly identify this compound as the first antihypertensive agent that modulates DDAH2 in endothelial cells.
Garbin
Ulisse
U
Department of Biomedical and Surgical Sciences, Section of Internal Medicine, University of Verona, Policlinico G.B. Rossi, Piazzale L.A. Scuro10, 37134 Verona, Italy.
Pasini
Anna Fratta
AF
Stranieri
Chiara
C
Manfro
Stefania
S
Boccioletti
Veronica
V
Cominacini
Luciano
L
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D001262:Atenolol / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology*; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D000068577:Nebivolol; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D001578:Benzopyrans; D004983:Ethanolamines; D012333:RNA, Messenger; D000068577:Nebivolol; C024917:symmetric dimethylarginine; D001262:Atenolol; C018524:N,N-dimethylarginine; D001120:Arginine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D000581:Amidohydrolases; C059999:dimethylargininase