title: Valsartan regulates the interaction of angiotensin II type 1 receptor and endothelial nitric oxide synthase via Src/PI3K/Akt signalling.
abstract: OBJECTIVE
  Valsartan, a selective angiotensin II type 1 receptor (AT1R) blocker, has beneficial effects in the cardiovascular system in part by its increase of nitric oxide (NO) bioavailability, yet the mechanisms are unclear. We investigated the molecular mechanisms underlying this effect in endothelial cells (ECs).
  
  
  RESULTS
  NO production was examined by Griess reagent assay, DAF-2 DA fluorescence staining and cGMP ELISA kits. Protein interaction was determined by western blotting and immunoprecipitation. Treating bovine or human aortic ECs with valsartan increased NO production, as evidenced by elevated level of stable NO metabolites and intracellular cGMP. Valsartan increased the phosphorylation but not the protein level of endothelial NO synthase (eNOS). Inhibition of phosphoinositide-3 kinase (PI3K)/Akt and Src pathways by specific inhibitors suppressed valsartan-induced NO release. In addition, valsartan increased the tyrosine residue phosphorylation of AT1R, which was attenuated by inhibition of Src but not PI3K activities. Valsartan also suppressed the interaction of eNOS and AT1R, which was blocked by Src or PI3K inhibition.
  
  
  CONCLUSIONS
  Valsartan-induced NO production in ECs is mediated through Src/PI3K/Akt-dependent phosphorylation of eNOS. Valsartan-induced AT1R phosphorylation depends on Src but not PI3K, whereas valsartan-induced suppression of AT1R-eNOS interaction depends on Src/PI3K/Akt signalling. These results indicate a novel vasoprotective mechanism of valsartan in upregulating NO production in ECs.
authors.affiliation: Department of Physiology, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Kuo-Hui
authors.initials: KH
authors.lastname: Su
authors.forename: Jin-Yi
authors.initials: JY
authors.lastname: Tsai
authors.forename: Yu Ru
authors.initials: YR
authors.lastname: Kou
authors.forename: An-Na
authors.initials: AN
authors.lastname: Chiang
authors.forename: Sheng-Huang
authors.initials: SH
authors.lastname: Hsiao
authors.forename: Yuh-Lin
authors.initials: YL
authors.lastname: Wu
authors.forename: Hsin-Han
authors.initials: HH
authors.lastname: Hou
authors.forename: Ching-Chian
authors.initials: CC
authors.lastname: Pan
authors.forename: Song-Kun
authors.initials: SK
authors.lastname: Shyue
authors.forename: Tzong-Shyuan
authors.initials: TS
authors.lastname: Lee
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D009569:Nitric Oxide; D000068756:Valsartan; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D014633:Valine