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Endothelial Nitric Oxide Synthase Enhancer AVE3085 Restores Endothelial Function in the Human Artery
Author(s) -
XUAN Chao,
LIU XiaoCheng,
BAI XiaoYan,
YANG Qin,
HE GuoWei
Publication year - 2011
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.25.1_supplement.810.3
Endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) is a cardiovascular risk factor. Increased ADMA levels are associated with reduced NO synthesis. We tested the effect of AVE3085, a novel compound enhancing endothelial NO synthase (eNOS) promoter activity, in human internal mammary artery (IMA) segments (n=8 in each group) in a myograph to establish cumulative concentration‐relaxation curves to acetylcholine (ACh, 10 −11 ‐10 −5 M) in U46619‐precontraction and protein expression of eNOS. The maximal relaxation to ACh (35.3±5.0% in control) was significantly attenuated by ADMA (12.7%±6.4%, P =0.002), but not by ADMA+AVE3085 (23.4±7.9%; P =0.1). Compared to ADMA alone, ADMA+AVE3085 significantly improved the relaxation ( P =0.001). The eNOS expression in IMA (0.36±0.03) was significantly decreased by ADMA (0.05±0.04, P =0.01) and markedly restored by AVE3085 (0.29±0.01; P =0.01). Thus, in the human arteries, AVE3085 may restore the reduced endothelium‐dependent relaxation through upregulation of eNOS expression. This may provide new therapeutic insights in clinical situations with eNOS downregulation. Supported by China Nat'l Ministry of Sci. & Tech. 2009DFB30560 & 2010CB529502 (973); Tianjin Municipal Sci. & Tech. Commission 09ZCZDSF04200 &10JCYBJC26400; Hong Kong RGC (CUHK4651/07M & CUHK4789/09M); CUHK2041561, and Providence SV Med. Foundation, Portland, OR.