Involvement of DDAH/ADMA/NOS pathway in nicotine-induced endothelial dysfunction.
Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, is a key contributor for endothelial dysfunction. Decrease in activity of dimethylarginine dimethylaminohydrolase (DDAH), a major hydrolase of ADMA, causes accumulation of ADMA under cardiovascular abnormalities. The study was to determine whether nicotine-induced endothelial dysfunction is related to modulating DDAH/ADMA/NOS pathway. Four-week oral nicotine treatment (5 mg/kg/day) significantly increased the plasma level of ADMA and decreased aortic DDAH expression as well as impaired endothelial function in Sprague-Dawley rats. Similarly, the medium levels of both ADMA and lactate dehydrogenase were markedly elevated in umbilical vein endothelial cells (HUVECs) treated with nicotine (10 microM) for 48 h. Nicotine-induced endothelial damages were markedly attenuated by L-arginine or overexpression of DDAH-II. Nicotine greatly downregulated both mRNA and protein levels of DDAH-II, and decreased DDAH activity in HUVECs. HUVECs express alpha7 nicotinic acetylcholine receptor (alpha7 nAChR), whose antagonists could block these effects of nicotine mentioned above. Intracellular Ca2+ chelator did not affect nicotine-induced decrease in DDAH-II mRNA level. In conclusion, nicotine modulates DDAH/ADMA/NOS pathway of endothelial cell via activation of alpha7 nAChR, which may be involved in endothelial dysfunction associated to smoking.
Jiang
De-Jian
DJ
Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China.
Jia
Su-Jie
SJ
Yan
Jin
J
Zhou
Zhi
Z
Yuan
Qiong
Q
Li
Yuan-Jian
YJ
D000581:Amidohydrolases / Q000502:physiology*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology*; D006801:Humans; D008297:Male; D009538:Nicotine / Q000378:metabolism* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism; D014652:Vascular Diseases / Q000473:pathology*
D012333:RNA, Messenger; D011978:Receptors, Nicotinic; C018524:N,N-dimethylarginine; D009538:Nicotine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000581:Amidohydrolases; C059999:dimethylargininase; D002118:Calcium