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Valsartan Regulates Interaction of Angiotensin II Type 1 Receptor and Endothelial Nitric Oxide Synthase via Src/PI3 K/Akt Signaling Pathway
Author(s) -
Su KuoHui,
Tsai JinYi,
Kou Yu Ru,
Wu YuhLin,
Shyue SongKun,
Lee TzongShyuan
Publication year - 2008
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.22.1_supplement.749.4
Subject(s) - valsartan , enos , angiotensin ii , protein kinase b , phosphorylation , proto oncogene tyrosine protein kinase src , ly294002 , nitric oxide , chemistry , tyrosine phosphorylation , endothelium , tyrosine kinase , medicine , nitric oxide synthase , pharmacology , microbiology and biotechnology , endocrinology , signal transduction , receptor , biochemistry , biology , blood pressure
Valsartan, a selective angiotensin II type 1 receptor (AT1R) blocker, lowers blood pressure by causing vascular smooth muscle cell relaxation and nitric oxide (NO) production in endothelium. However, the underlying mechanisms of valsartan on NO production are not fully understood. In this study, we sought to investigate the molecular mechanism of valsartan in activation of endothelial nitric oxide synthase (eNOS) in bovine aortic endothelial cells (BAECs). Treatment with valsartan increased NO production in a dose‐ and time‐dependent manner, while the protein level of eNOS was not affected. Furthermore, valsartan increased the phosphorylated levels of Akt and eNOS proteins. Specific inhibitors were utilized to clarify the critical kinases involved in valsartan‐mediated eNOS activation. Our results showed that LY294002, a PI3 kinase antagonist and SU6656, a Src kinase family antagonist markedly suppressed valsartan‐induced eNOS phosphorylation and NO production. On the other hand, we also found valsartan treatment increased phosphorylation of AT1R on tyrosine residues and reduced association of eNOS and AT1R. Pretreatment with SU6656, but not LY294002 reversed this dissociation between eNOS and AT1R, implying the requirement of tyrosine phosphorylation on AT1R for valsartan‐mediated reduction of eNOS‐AT1R interaction. Take together, our findings suggest that valsartan induced eNOS activation through Src/PI3/Akt signaling pathway and regulation on AT1R‐eNOS interaction.