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Mechanisms of AVE3085 Against Asymmetrical Dimethylarginine‐induced Endothelial Dysfunction
Author(s) -
Xue HongMei,
He GuoWei,
Huang JunHao,
Yang Qin
Publication year - 2010
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.24.1_supplement.959.3
Subject(s) - enos , medicine , endothelial dysfunction , endocrinology , asymmetric dimethylarginine , nitric oxide synthase type iii , nitrotyrosine , nitric oxide , endothelium , nitric oxide synthase , chemistry , endogeny , endothelial nitric oxide synthase , arginine , biochemistry , amino acid
Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS) that may induce endothelial dysfunction. We studied the effect and mechanism of AVE3085, a newly developed transcription enhancer of endothelial NOS (eNOS), on ADMA‐induced coronary endothelial dysfunction. Porcine coronary small arteries were studied for endothelium‐dependent and ‐independent relaxations. Protein expressions of eNOS and nitrotyrosine as well as eNOS phosphorylation at serine 1177 (p‐eNOS Ser1177 ) and threonine 495 (p‐eNOS Thr495 ) were determined. ADMA treatment for 1‐hr significantly decreased endothelium‐dependent relaxation to bradykinin (61.3±4.7% vs. 92.2±2.6%, EC 50 : −7.04±0.16 vs. −7.80±0.14 LogM, p <0.05) that was preserved by the co‐treatment of AVE3085 (86.7±3.2%, −7.67±0.22 LogM). ADMA markedly reduced the protein expression of eNOS and p‐eNOS Ser1177 whereas increased the expression of p‐eNOS Thr495 and nitrotyrosine ( p <0.05). The decreased expression of eNOS and p‐eNOS Ser1177 was reversed by AVE3085. AVE3085 also lowered the expression of p‐eNOS Thr495 and nitrotyrosine ( p <0.05). AVE3085 prevents ADMA‐induced coronary endothelial dysfunction. Enhancements of eNOS expression and activation as well as reduction of oxidative stress underline the protection of AVE3085. Supported by Hong Kong GRF grants CUHK4651/07M & 4789/09M and CUHK direct grant 2041457.