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Mechanistic Studies of AVE3085 Against Homocysteine in Endothelial Protection.
- Source :
- Cardiovascular Drugs & Therapy; Dec2013, Vol. 27 Issue 6, p511-520, 10p
- Publication Year :
- 2013
-
Abstract
- Purpose: Homocysteine (Hcy) is an independent risk factor for cardiovascular diseases that impairs endothelial function. We investigated whether the impaired endothelial function can be restored by the eNOS transcription enhancer AVE3085 in porcine coronary arteries. The effects of AVE3085 against Hcy on eNOS-NO function were studied and further investigations were conducted to reveal the role of arginase and the signaling pathway of eNOS activation in the effect of AVE3085 on endothelial dysfunction caused by Hcy. Methods: Myograph study of vasorelaxation, 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 <subscript>2</subscript><superscript>.−</superscript> generation by lucigenin-enhanced chemiluminenscence. Results: Exposure to Hcy for 24 h attenuated bradykinin-induced relaxation and NO release, downregulated eNOS mRNA expression and protein expressions of eNOS and p-eNOS <superscript>Ser1177</superscript> whereas it upregulated iNOS expression. AVE3085 restored NO release and relaxation, enhanced eNOS but decreased iNOS expression. Inhibition of protein kinase Akt or PI3 kinase attenuated the effect of AVE3085 on relaxation and eNOS phosphorylation. Arginase activity and O <subscript>2</subscript><superscript>.−</superscript> production were inhibited by AVE3085 in Hcy-exposed vessels. Conclusions: AVE3085 prevents Hcy-induced endothelial dysfunction in coronary arteries by preservation of NO production and suppression of O <subscript>2</subscript><superscript>.−</superscript> generation. Preservation of NO is attributed to upregulation of eNOS expression, activation of eNOS via phosphorylation of Ser1177 through a PI3 kinase/Akt-dependent pathway, and inhibition of arginase. Reduction of O <subscript>2</subscript><superscript>.−</superscript> generation results from reversal of eNOS uncoupling and inhibition of arginase and iNOS. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09203206
- Volume :
- 27
- Issue :
- 6
- Database :
- Complementary Index
- Journal :
- Cardiovascular Drugs & Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 91988766
- Full Text :
- https://doi.org/10.1007/s10557-013-6478-5