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(Circulation Research. 1999;84:876-882.)
© 1999 American Heart Association, Inc.

Original Contribution

Stimulation of Different Subtypes of Angiotensin II Receptors, AT₁ and AT₂ Receptors, Regulates STAT Activation by Negative Crosstalk

Masatsugu Horiuchi, Wataru Hayashida, Masahiro Akishita, Kouichi Tamura, Laurent Daviet, Jukka Y. A. Lehtonen, Victor J. Dzau

From Cardiovascular Research, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Mass.

Correspondence to Masatsugu Horiuchi, MD, PhD, Department of Medical Biochemistry, Ehime University School of Medicine, Sigenobu, Onsen-gun, Ehime 791-0295, Japan. E-mail horiuchi{at}m.ehime-u.ac.jp

Abstract—Angiotensin II type 2 (AT₂) receptor exerts an inhibitory action on cell growth. In the present study, we report that the stimulation of AT₂ receptor in AT₂ receptor cDNA–transfected rat adult vascular smooth muscle cells (VSMCs) inhibited angiotensin II type 1 (AT₁) receptor–mediated tyrosine phosphorylation of STAT (signal transducers and activators of transcription) 1/ß, STAT2, and STAT3 without influence on Janus kinase. AT₂ receptor activation also inhibited the tyrosine phosphorylation of STAT1/ß induced by interferon-, epidermal growth factor, and platelet-derived growth factor. Similar effects of AT₂ receptor were observed in R3T3 fibroblast and mouse fetal VSMCs, which express endogenous AT₂ receptor. Moreover, AT₂ receptor inhibited serine phosphorylation of STAT1 and STAT3 via the inhibition of extracellular signal–regulated kinase (ERK) activation. Stimulation of AT₂ receptor inhibited the binding of STATs with sis-inducing element in c-fos promoter, resulting in decreased c-fos expression. Taken together, our results suggest that AT₂ receptor can crosstalk negatively with multiple families of growth receptors by inhibiting ERK and STAT activation.

Key Words: angiotensin • receptor • STAT • vascular smooth muscle cell

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