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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2119-2126.)
© 1999 American Heart Association, Inc.

Vascular Biology

Angiotensin II Activation of Insulin-Like Growth Factor 1 Receptor Transcription Is Mediated by a Tyrosine Kinase–Dependent Redox-Sensitive Mechanism

Jie Du; Tao Peng; Kathrin J. Scheidegger; Patrick Delafontaine

From Emory University, Atlanta, Ga (J.D., T.P.), and the Division of Cardiology, University Hospital of Geneva, Switzerland (K.J.S., P.D.).

Abstract—We have recently shown that angiotensin II activation of insulin-like growth factor 1 receptor (IGF-1R) transcription is a critical requirement for angiotensin-stimulated vascular smooth muscle cell growth; therefore, we examined the signaling pathway involved. In rat aortic smooth muscle cells, the antioxidants N-acetyl-L-cysteine (5 mmol/L) and pyrrolidine dithiocarbamate (100 µmol/L) completely inhibited angiotensin II–stimulated increases in IGF-1R mRNA and protein levels, suggesting the involvement of reactive oxygen species. Indeed, catalase abolished the Ang II–stimulated increase of IGF-1R protein expression, and accordingly, H₂O₂ (0.2 mmol/L) or the oxidized products of linoleic acid, hydroperoxyoctadecadienoic acids (10 µmol/L), increased IGF-1R mRNA levels at 3 hours by 74±20% and 107±22% and increased receptor number at 24 hours by 51±6.7% and 55±7.4%, respectively. The protein tyrosine kinase inhibitors genistein and tyrphostin A25 also blocked angiotensin II increases in IGF-1R mRNA and protein levels and blocked the ability of hydroperoxyoctadecadienoic acids and H₂O₂ to increase IGF-1R expression, suggesting that oxidative stress may be an early event in the angiotensin II signaling cascade. Furthermore, calcium chelation inhibited the angiotensin II effect. Transient transfection assays revealed that a -2350/+640 IGF-1R promoter/luciferase construct was fully responsive to angiotensin II stimulation (127±20% increase). Ten millimoles per liter hydroperoxyoctadecadienoic acids and 0.2 mmol/L H₂O₂ increased luciferase activity by 79±8.5% and 63±12%, respectively, and 5 mmol/L N-acetyl-L-cysteine blocked the angiotensin II–induced upregulation of luciferase activity by 70%. These data suggest that angiotensin II stimulates IGF-1R gene transcription via calcium-dependent activation of protein tyrosine kinase activity that lies downstream from an oxidant stimulus. These findings provide key insights into the signaling mechanisms whereby angiotensin II exerts its growth-promoting effects on the vasculature.

Key Words: insulin-like growth factor 1 receptor • reactive oxygen species • tyrosine kinases • gene regulation • signal transduction

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