Involvement of the endothelial DDAH/ADMA pathway in nitroglycerin tolerance: the role of ALDH-2.
Previous studies have shown that nitroglycerin (GTN) tolerance is closely related to an oxidative stress-induced decrease in activity of mitochondrial isoforms of aldehyde dehydrogenase (ALDH-2), and prolonged GTN treatment causes endothelial dysfunction. Asymmetric dimethylarginine (ADMA), a major endogenous NO synthase (NOS) inhibitor, could inhibit NO production and induce oxidative stress in endothelial cells. ADMA and its major hydrolase dimethylarginine dimethylaminohydrolase (DDAH) have recently been thought of as a novel regulatory system of endothelium function. The aim of the present study was to determine whether the DDAH/ADMA pathway is involved in the development of GTN tolerance in endothelial cells. Tolerance, reflected by the decrease in cyclic GMP (cGMP) production, was induced by exposure of human umbilical vein endothelial cells (HUVECs) to GTN (10 microM) for 16 h. While the treatment increased reactive oxygen species (ROS) production/malondialdehyde (MDA) concentration and decreased ALDH-2 activity as well as cGMP production, it markedly increased the level of ADMA in culture medium and decreased DDAH activity in endothelial cells. Exogenous ADMA significantly enhanced ROS production/MDA concentration and inhibited ALDH-2 activity, and overexpression of DDAH2 could significantly suppress GTN-induced oxidative stress and inhibition of ALDH-2 activity, which is also attenuated by L-arginine. Therefore, our results suggest for the first time that the endothelial DDAH/ADMA pathway plays an important role in the development/maintenance of GTN tolerance.
Zhang
Guo-Gang
GG
Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Shi
Rui-Zheng
RZ
Jiang
De-Jian
DJ
Chen
Yue-Rong
YR
Jia-Chen
Tang
Zheng-Yan
ZY
Bai
Yong-Ping
YP
Xiao
Hong-Bo
HB
Li
Yuan-Jian
YJ
D000111:Acetylcysteine / Q000494:pharmacology; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000502:physiology*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000581:Amidohydrolases / Q000096:biosynthesis / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism; D004361:Drug Tolerance; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008054:Lipid Peroxides / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D005996:Nitroglycerin / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
D008054:Lipid Peroxides; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; C018524:N,N-dimethylarginine; D001120:Arginine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000581:Amidohydrolases; C059999:dimethylargininase; D005996:Nitroglycerin; D006152:Cyclic GMP; D000111:Acetylcysteine