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

• Published in: Cardiovascular research Vol. 82; no. 3; pp. 468 - 475
• Main Authors: Su, Kuo-Hui, Tsai, Jin-Yi, Kou, Yu Ru, Chiang, An-Na, Hsiao, Sheng-Huang, Wu, Yuh-Lin, Hou, Hsin-Han, Pan, Ching-Chian, Shyue, Song-Kun, Lee, Tzong-Shyuan
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.06.2009
• Subjects: Animals; Antihypertensive Agents - pharmacology; Aorta - cytology; AT1R; Biological and medical sciences; Cardiology. Vascular system; Cattle; Cells, Cultured; Endothelial Cells - metabolism; eNOS; Humans; Medical sciences; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; PI3K; Proto-Oncogene Proteins c-akt - metabolism; Receptor, Angiotensin, Type 1 - metabolism; Signal Transduction; Src family kinase; src-Family Kinases - metabolism; Tetrazoles - pharmacology; Valine - analogs & derivatives; Valine - pharmacology; Valsartan; R; eNOS; AT; Valsartan; PI3K; Src family kinase; Angiotensin II receptor; Enzyme; Family study; Transferases; Phlebology; Nitric-oxide synthase; Regulation(control); Type; Kinase; Family environment; Oxidoreductases; Circulatory system; Cardiology
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvp091

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.