Involvement of DDAH/ADMA/NOS pathway in nicotine-induced endothelial dysfunction
Involvement of DDAH/ADMA/NOS pathway in nicotine-induced endothelial dysfunction
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DOI：
10.1016/j.bbrc.2006.08.115
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发表时间：
2006-10-20
影响因子：
3.1
通讯作者：
Li, Yuan-Jian
中科院分区：
文献类型：
--
作者：
Jiang, De-Jian;Jia, Su-Jie;Li, Yuan-Jian
不对称二甲基精氨酸（ADMA）是一种内源性一氧化氮合酶（NOS）抑制剂，是内皮功能障碍的关键因素。二甲基精氨酸二甲氨基水解酶（DDAH）是ADMA的主要水解酶，其活性降低可导致心血管异常时ADMA蓄积。本研究旨在探讨尼古丁诱导的内皮功能障碍是否与调节DDAH/ADMA/NOS通路有关。经口给予尼古丁4周（5 mg/kg/天）显著增加了Sprague-Dawley大鼠的ADMA血浆水平，降低了主动脉DDAH表达，并损害了血管内皮功能。同样，ADMA和乳酸脱氢酶的介质水平显着升高，在脐静脉内皮细胞（HUVECs）与尼古丁（10 μ M）治疗48 It。尼古丁诱导的血管内皮损伤显着减弱L-精氨酸或过表达DDAH-II。尼古丁显著下调HUVECs中DDAH-Ⅱ的mRNA和蛋白水平，并降低DDAH活性。HUVECs表达α 7烟碱乙酰胆碱受体（0 nAChR），其拮抗剂可阻断尼古丁的上述作用。细胞内钙离子螯合剂不影响尼古丁诱导的DDAH-Ⅱ mRNA水平的下降。结论：尼古丁通过激活α 7 nAChR调节血管内皮细胞DDAH/ADMA/NOS通路，可能参与吸烟相关的血管内皮功能障碍。(c)2006爱思唯尔公司All rights reserved.
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 enclothelial 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 mu M) for 48 It. Nicotine-induced enclothelial 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 alpha 7 nicotinic acetylcholine receptor (0 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 enclothelial cell via activation of alpha 7 nAChR, which may be involved in enclothelial dysfunction associated to smoking. (c) 2006 Elsevier Inc. All rights reserved.