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Cardiovascular Research Advance Access first published online on March 23, 2009
This version [Corrected Proof] published online on April 2, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp091
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Valsartan regulates the interaction of angiotensin II type 1 receptor and endothelial nitric oxide synthase via Src/PI3K/Akt signalling

Kuo-Hui Su1,{dagger}, Jin-Yi Tsai1,{dagger}, Yu Ru Kou1, An-Na Chiang2, Sheng-Huang Hsiao3, Yuh-Lin Wu1, Hsin-Han Hou1, Ching-Chian Pan1, Song-Kun Shyue4,* and Tzong-Shyuan Lee1,*

1 Department of Physiology, National Yang-Ming University, Taipei, Taiwan, ROC
2 Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, ROC
3 Department of Surgery, Ren-Ai Taipei City Hospital, Taipei, Taiwan, ROC
4 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC

* Corresponding author. Tel: +886 2 2826 7365 (T.-S.L.)/+886 2 2652 3962 (S.-K.S.); fax: +886 2 2826 4049 (T.-S.L.)/+886 2 2785 8594 (S.-K.S.). E-mail address: tslee{at}ym.edu.tw(T.-S.L.)/skshyue{at}ibms.sinica.edu.tw (S.-K.S.)

Aims: 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).

Methods and 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.

Conclusion: 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.

KEYWORDS Valsartan; PI3K; Src family kinase; AT1R; eNOS

Time for primary review: 33 days

{dagger} The first two authors equally contributed to this work.


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