title: Demethylation treatment restores erectile function in a rat model of hyperhomocysteinemia.
abstract: Methylation modification is an important cellular mechanism of gene expression regulation. Dimethylarginine dimethylaminohydrolase-2 (DDAH-2) protein is a pivotal molecular for endothelium function. To explore the effects of 5-aza-deoxycytidine (5-aza), a demethylation agent, in hyperhomocysteinemia (hhcy)-related erectile dysfunction (ED) rats, 5-aza (1 mg kg-1 ) was administrated to Sprague-Dawley hhcy-rats induced by supplemented methionine chow diet. Erectile function, nitric oxide-cyclic guanosine monophosphate (NO-cGMP) levels, expression of DDAH-2 protein and promoter methylation status of DDAH-2 were studied in the corpora cavernosa. We found that supplemented methionine diet induced a high homocysteine level after 6 weeks of treatment. DDAH-2 protein was down-regulated in the corpora cavernosa while the administration of 5-aza up-regulated DDAH-2 expression and restored erectile function. The methionine-fed rats showed high methylation levels of DDAH-2 promoter region while the group treated with 5-aza demonstrated lower-methylation levels when compared to the methionine-fed group. Besides, the administration of 5-aza improved NO and cGMP levels in methionine-fed rats. Therefore, the methylation mechanism involves in ED pathogenesis, and demethylation offers a potential new strategy for ED treatment.
authors.affiliation: Department of Andrology, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Andrology, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Zhu
authors.affiliation: Department of Andrology, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: He-Song
authors.initials: HS
authors.lastname: Jiang
authors.affiliation: Department of Andrology, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Andrology, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Andrology, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Yu-Tian
authors.initials: YT
authors.lastname: Dai
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001374:Azacitidine / Q000627:therapeutic use*; D006152:Cyclic GMP / Q000097:blood; D004195:Disease Models, Animal; D015536:Down-Regulation; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000209:etiology; D006710:Homocysteine / Q000097:blood*; D020138:Hyperhomocysteinemia / Q000150:complications / Q000188:drug therapy*; D008297:Male; D009569:Nitric Oxide / Q000097:blood; D010413:Penis / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D006710:Homocysteine; D009569:Nitric Oxide; D000581:Amidohydrolases; C059999:dimethylargininase; D006152:Cyclic GMP; D001374:Azacitidine