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Mechanistic Studies of AVE3085 Against Homocysteine in Endothelial Protection
Author(s) -
Yang Qin,
Xue HongMei,
Yu CheukMan
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.900.1
Subject(s) - enos , arginase , endothelial dysfunction , protein kinase b , medicine , chemistry , endocrinology , nitric oxide , endothelial nos , western blot , phosphorylation , nitric oxide synthase , biochemistry , arginine , amino acid , gene
The effect and mechanisms of eNOS transcription enhancer AVE3085 on homocysteine (Hcy)‐induced endothelial dysfunction were studied in porcine coronary small arteries. Myograph study of relaxation, electrochemical measurement of NO, RT‐PCR and Western blot analysis of eNOS, iNOS expression, and eNOS phosphorylation were performed. Arginase activity was determined by urea production and O 2 .− generation by lucigenin‐enhanced chemiluminenscence. Exposure to Hcy for 24h attenuated bradykinin‐induced relaxation and NO release, lowered eNOS mRNA, eNOS protein, and p‐eNOS Ser1177 whereas elevated iNOS level. AVE3085 restored NO release and relaxation, enhanced eNOS but decreased iNOS expression. Inhibition of Akt or PI3 kinase attenuated the effect of AVE3085 on relaxation and eNOS phosphorylation. Arginase activity and O 2 .− production were inhibited by AVE3085 in Hcy‐exposed vessels. AVE3085 prevents Hcy‐induced endothelial dysfunction by preservation of NO and inhibition of O 2 .− production. The preservation of NO‐related function is attributed to upregulation and activation of eNOS and inhibition of arginase. Reduction of O 2 .− results from reversal of eNOS uncoupling by inhibition of arginase and iNOS. PI3 kinase/Akt pathway is involved in AVE3085‐induced eNOS activation. Supported by GRF CUHK4789/09M & 4774/12M; NSFC 81200123; Key Med. Program of Tianjin Binhai Health Bureau 2011BHKZ001.