All-trans retinoic acid inhibits cobalt chloride-induced apoptosis in PC12 cells: role of the dimethylarginine dimethylaminohydrolase/asymmetric dimethylarginine pathway.

Previous studies have shown that the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its specific hydrolase dimethylarginine dimethylaminohydrolase (DDAH) are involved in the regulation of apoptosis in different cell types. In the present study, we investigated the role of the DDAH/ADMA pathway in cobalt chloride (CoCl(2))-induced apoptosis and the antiapoptotic effect of all-trans retinoic acid (atRA) in undifferentiated pheochromocytoma (PC12) cells. Treatment of CoCl(2) (125 microM) for 48 hr significantly induced the apoptosis of PC12 cells, concomitantly with increased intracellular reactive oxygen species (ROS) production and caspase-3 activity. CoCl(2) treatment also decreased the activity of DDAH and the expression of DDAH2 (mRNA and protein), resulting in an increased level of ADMA. All these alterations induced by CoCl(2) were attenuated by atRA (0.1, 1, or 10 microM). Interestingly, the antiapoptotic effects of atRA were inhibited by DDAH2 small RNA interference. In contrast, DDAH2 overexpression inhibited the proapoptotic effects of CoCl(2). We also found that treatment of exogenous ADMA (3, 10, or 30 microM) induced the apoptosis of PC12 cells in a concentration- and time-dependent manner, which was inhibited by the antioxidant or the caspase-3 inhibitor. These findings suggest that the modulation of the DDAH/ADMA/ROS pathway plays an important role in CoCl(2)-induced apoptosis and the antiapoptotic effects of atRA in undifferentiated PC12 cells.

Wang S ，Hu CP ，Jiang DJ ，Peng J ，Zhou Z ，Yuan Q ，Nie SD ，Jiang JL ，Li YJ ，Huang KL ... -  《-》

Homocysteine increases the production of asymmetric dimethylarginine in cultured neurons.

Increased circulating concentrations of homocysteine may be a risk factor for Alzheimer's disease and cognitive dysfunction in normal aging. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase (NOS). ADMA is metabolized in neurons by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Nitric oxide plays an important role in synaptic events involved in learning and memory. We determined the effect of L-homocysteine on ADMA accumulation and nitric oxide production in cultured rat neuronal granule cells. The incubation of neuronal granule cells with L-homocysteine for 24 hr caused a dose-dependent accumulation of ADMA and a dose-dependent decrease in nitric oxide production. The addition of the sulfhydryl antioxidant pyrrolidine dithiocarbamate (PDTC) attenuated the effect of homocysteine on ADMA accumulation and nitric oxide production. DDAH activity had a decreasing dose-response relationship with increasing L-homocysteine concentrations. The addition of PDTC caused a dose-dependent increase in DDAH activity. The addition of the N-methyl-D-aspartate receptor antagonists (+/-)-2-amino-5-phosphopentanoic acid and 7-chlorokynurenate had no effect on the inhibition of DDAH by homocysteine. It is concluded that L-homocysteine inhibits DDAH activity, thereby causing ADMA accumulation and decreasing nitric oxide production in cultured neurons. The protective effect of PDTC suggests that L-homocysteine inactivates DDAH in neurons by reacting with the cysteine residue in its active site. The preservation of DDAH activity and the reduction of ADMA accumulation in neurons may be a new strategy for the treatment of Alzheimer's disease and cognitive impairment in normal aging.

Selley ML 《JOURNAL OF NEUROSCIENCE RESEARCH》

Estradiol protects PC12 cells against CoCl2-induced apoptosis.

Jung JY ，Roh KH ，Jeong YJ ，Kim SH ，Lee EJ ，Kim MS ，Oh WM ，Oh HK ，Kim WJ ... -  《-》

Inhibitory effect of resveratrol derivative BTM-0512 on high glucose-induced cell senescence involves dimethylaminohydrolase/asymmetric dimethylarginine pathway.

Yuan Q ，Peng J ，Liu SY ，Wang CJ ，Xiang DX ，Xiong XM ，Hu CP ，Li YJ ... -  《-》

Involvement of the endothelial DDAH/ADMA pathway in nitroglycerin tolerance: the role of ALDH-2.

Zhang GG ，Shi RZ ，Jiang DJ ，Chen YR ，Jia-Chen ，Tang ZY ，Bai YP ，Xiao HB ，Li YJ ... -  《LIFE SCIENCES》