Published Online
on September 25, 2006

A more recent version of this article appeared on November 1, 2006

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Submitted on June 12, 2006
Revised on July 5, 2006

Angiotensin II Stimulates Endothelial NO Synthase Phosphorylation in Thoracic Aorta of Mice With Abdominal Aortic Banding Via Type 2 Receptor

Katsutoshi Yayama; Hiromi Hiyoshi; Daichi Imazu; and Hiroshi Okamoto^*

From the Laboratory of Cardiovascular Pharmacology, Department of Biopharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan.

^* To whom correspondence should be addressed. E-mail: okamotoh{at}pharm.kobegakuin.ac.jp.

Abstract--Abdominal aortic banding in mice induces upregulation of angiotensin II (Ang II) type 2 (AT₂) receptors in the pressure-overloaded thoracic aorta. To clarify mechanisms underlying the vascular AT₂ receptor-dependent NO production, we measured aortic levels of endothelial NO synthase (eNOS), eNOS phosphorylated at Ser⁶³³ and Ser¹¹⁷⁷, protein kinase B (Akt), and Akt phosphorylated at Ser⁴⁷³ in thoracic aortas of mice after banding. Total eNOS, both forms of phosphorylated eNOS, Akt, and phosphorylated Akt levels, as well as cGMP contents, were significantly increased 4 days after banding. The administration of PD123319 (an AT₂ receptor antagonist) or icatibant (a bradykinin B₂ receptor antagonist) abolished the banding-induced upregulation of both forms of phosphorylated eNOS, as well as elevation of cGMP, but did not affect the upregulation of eNOS, Akt, and phosphorylated Akt. In the in vitro experiments using aortic rings prepared from banded mice, Ang II produced significant increases in both forms of phosphorylated eNOS, as well as cGMP, and these effects were blocked by PD123319 and icatibant. Ang II-induced eNOS phosphorylation and cGMP elevation in aortic rings were inhibited by protein kinase A (PKA) inhibitors H89 and KT5720 but not by phosphatidylinositol 3-kinase inhibitors wortmannin and LY24002. The contractile response to Ang II was attenuated in aortic rings from banded mice via AT₂ receptor, and this attenuation was blocked by PKA inhibitors. These results suggest that the activation of AT₂ receptor by Ang II induces phosphorylation of eNOS at Ser⁶³³ and Ser¹¹⁷⁷ via a PKA-mediated signaling pathway, resulting in sustained activation of eNOS.

Key words: angiotensin II type 2 receptor • endothelial nitric oxide synthase • bradykinin • signal transduction

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