Pivotal role of tyrosine phosphatase SHP-1 in AT2 receptor-mediated apoptosis in rat fetal vascular smooth muscle cell

doi:10.1016/S0008-6363(00)00299-6

Cardiovascular Research 2001 49(4):863-871; doi:10.1016/S0008-6363(00)00299-6
© 2001 by European Society of Cardiology

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Pivotal role of tyrosine phosphatase SHP-1 in AT2 receptor-mediated apoptosis in rat fetal vascular smooth muscle cell

Tai-Xing Cui^a, Hironori Nakagami^a, Masaru Iwai^a, Yuko Takeda^a, Tetsuya Shiuchi^a, Laurent Daviet^b^,c, Clara Nahmias^d and Masatsugu Horiuchi^a^,*

^aDepartment of Medical Biochemistry, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime 791-0295, Japan
^bCardiovascular Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
^cHybrigenics SA, Paris, France
^dCNRS UPR0415 — Institut Cochin de Genetique Moleculaire, Paris, France

^* Corresponding author. Tel.: +81-89-960-5249; fax: +81-89-960-5251 horiuchi{at}m.ehime-u.ac.jp

Objective: To examine the possible crosstalk and the roles ofangiotensin (Ang) II type 1 (AT1) and type 2 (AT2) receptorsin the control of apoptosis in fetal vascular smooth musclecells (VSMCs). Methods: Fetal VSMCs were prepared from rat fetalaorta at embryonic day 20. Expression of Ang II receptors wasmeasured by a radioligand binding assay. Apoptotic changes wereassessed by caspase 3 activity and chromatin dye staining. Regulationof extracellular signal-regulated kinase (ERK) activity viaAng II receptors was analysed by determinating phosphorylatedERK with Western blot. Ang II receptor-mediated activation oftyrosine phosphatase SHP-1 was assessed by protein tyrosinephosphatase assay. Results: The expression of AT1 and AT2 receptorswas approximately 70%: 30% per cell. Serum depletion inducedapoptosis in fetal VSMCs and selective AT1 receptor stimulationattenuated the apoptotic changes, whereas selective AT2 receptoractivation enhanced apoptosis. Ang II increased ERK phosphorylation,which was inhibited by addition of the AT1 receptor-specificantagonist CV11974, but enhanced by addition of the AT2 receptor-specificantagonist PD123319, suggesting that activation of AT2 receptorattenuated the AT1 receptor-mediated ERK phosphorylation. Moreover,we demonstrated that AT2 receptor stimulation activated SHP-1in fetal VSMCs, whereas AT1 receptor stimulation did not. Transienttransfection of a dominant-negative SHP-1 mutant into rat fetalVSMCs resulted in a significant decrease of the AT2 receptor-mediatedinhibition of ERK phosphorylation and attenuated the proapoptoticeffect of AT2 receptor. Conclusion: These results indicate thata crosstalk between AT1 and AT2 receptors regulates the survivalof fetal VSMCs and substantiate SHP-1 as a key molecule in AT2receptor signaling.

KEYWORDS Angiotensin; Apoptosis; Receptor; Signal transduction; Smooth muscle

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