PMID- 18167189
OWN - NLM
STAT- MEDLINE
DCOM- 20080205
LR  - 20161124
IS  - 0366-6999 (Print)
IS  - 0366-6999 (Linking)
VI  - 120
IP  - 23
DP  - 2007 Dec 5
TI  - Dysfunction of endothelial NO system originated from homocysteine-induced 
      aberrant methylation pattern in promoter region of DDAH2 gene.
PG  - 2132-7
AB  - BACKGROUND: Hyperhomocysteinemia (HHcy)-mediated dysfunction of endothelial NO 
      system is an important mechanism for atherosclerotic pathogenesis. 
      Dimethylarginine dimethylaminohydrolase (DDAH) is the key enzyme for degrading 
      asymmetric dimethylarginine (ADMA), which is an endogenous inhibitor of 
      endothelial nitric oxide (NO) synthase (eNOS). This study was designed to 
      investigate whether the dysfunction of endothelial NO system originates from 
      HHcy-mediated aberrant methylation modification in promotor region of DDAH2 gene. 
      METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured to the 
      third generation and treated with homocysteine (Hcy) at different concentrations 
      (0, 10, 30, 100, and 300 micromol/L) for 72 hours. The methylation pattern in 
      promoter region CpG island of DDAH2 gene was analyzed by nested 
      methylation-specific PCR (nMSP). The mRNA expression of eNOS gene and DDAH2 gene 
      was detected by semi-quantitative RT-PCR. The activity of DDAH2 and eNOS in 
      cells, and the concentrations of ADMA and NO in culture medium were assayed 
      respectively. RESULTS: Mild increased concentration of Hcy (10 and 30 micromol/L) 
      induced hypomethylation, while high concentration of Hcy (100 and 300 micromol/L) 
      induced hypermethylation in the promoter CpG island of DDAH2 gene. The mRNA 
      expression of DDAH2 increased in mild enhanced concentration of Hcy, and 
      decreased in high concentration of Hcy correspondingly. The inhibition of DDAH2 
      activity, the increase of ADMA concentration, the reduction of eNOS activity and 
      the decrease of NO production were all consistently relevant to the alteration of 
      Hcy concentration. CONCLUSION: The increased concentration of Hcy induced 
      aberrant methylation pattern in promotor region of DDAH2 gene and the successive 
      alterations in DDAH/ADMA/NOS/NO pathway, which showed highly relevant and 
      dose-effect relationship. The results suggested that the dysfunction of 
      endothelial NO system induced by HHcy could be partially originated from 
      Hcy-mediated aberrant methylation in DDAH2 gene.
FAU - Zhang, Jing-ge
AU  - Zhang JG
AD  - Department of Pathophysiology, West China School of Preclinic Medical Sciences 
      and Forensic Medicine, Sichuan University, Chengdu, China.
FAU - Liu, Jun-xu
AU  - Liu JX
FAU - Li, Zhu-hua
AU  - Li ZH
FAU - Wang, Li-zhen
AU  - Wang LZ
FAU - Jiang, Yi-deng
AU  - Jiang YD
FAU - Wang, Shu-ren
AU  - Wang SR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - China
TA  - Chin Med J (Engl)
JT  - Chinese medical journal
JID - 7513795
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 63CV1GEK3Y (N,N-dimethylarginine)
RN  - 94ZLA3W45F (Arginine)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 3.5.- (Amidohydrolases)
RN  - EC 3.5.3.18 (dimethylargininase)
SB  - IM
MH  - Amidohydrolases/*genetics
MH  - Arginine/analogs & derivatives/blood
MH  - Cells, Cultured
MH  - DNA Methylation/*drug effects
MH  - Homocysteine/*pharmacology
MH  - Humans
MH  - Nitric Oxide/analysis/*physiology
MH  - Nitric Oxide Synthase Type III/genetics/*physiology
MH  - *Promoter Regions, Genetic
EDAT- 2008/01/03 09:00
MHDA- 2008/02/06 09:00
CRDT- 2008/01/03 09:00
PHST- 2008/01/03 09:00 [pubmed]
PHST- 2008/02/06 09:00 [medline]
PHST- 2008/01/03 09:00 [entrez]
PST - ppublish
SO  - Chin Med J (Engl). 2007 Dec 5;120(23):2132-7.