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Angiotensin II Stimulates Transcription of Insulin-Like Growth Factor I Receptor in Vascular Smooth Muscle Cells: Role of Nuclear Factor-B

Department of Medicine (Y.M., L.Z., T.P., J.C., S.T., J.Z., J.D.), Baylor College of Medicine, Houston, Texas 77030; and Department of Internal Medicine (P.D.), Tulane University, New Orleans, Louisiana 70131

Address all correspondence and requests for reprints to: Dr. Jie Du, Mail stop BCM285, Department of Medicine, One Baylor Plaza, N520, Baylor College of Medicine, Houston, Texas 77030. E-mail: jdu{at}bcm.edu.

Increased expression of the IGF-I receptor (IGF-IR) is associated with proliferation and survival of vascular smooth muscle cells (VSMCs). In cultured VSMCs, we reported that angiotensin II (Ang II) increases transcription and expression of IGF-IR. Now, we show that mesenteric arteries of rats infused with Ang II develop thickening and increased IGF-IR expression. To determine how Ang II transcriptionally regulates IGF-IR expression in VSMCs, we generated 5'-end deletions of the IGF-IR promoter and measured Ang II-induced promoter-luciferase activity in VSMCs. Activities from these promoter sequences suggested that the Ang II-responsive region is located between –270 and –135 of the IGF-IR promoter. Using a DNase I foot printing analysis, we identified two putative nuclear factor-B (NF-B)-like sequences located in the same region of the IGF-IR promoter. When we mutated either of these NF-B-like sites, Ang II-induced IGF-IR promoter activity decreased sharply. Electrophoretic mobility gel shift, anti-p50 of NF-B supershift and chromatin immunoprecipitation assays demonstrated that both the p65 and p50 subunits of NF-B will bind to this Ang II response element in the IGF-IR promoter. When we blocked the Ras/MAPK kinase 1 pathway or the inhibitory-B kinase pathway, both Ang II-induced IGF-IR promoter activity and expression of IGF-IR protein significantly declined. Our results indicate that the mechanism by which Ang II stimulates IGF-IR expression in VSMCs involves NF-B binding to NF-B sites in the IGF-IR promoter, leading to expression of IGF-IR through both Ras/MAPK kinase 1-and inhibitory-B kinase-dependent pathways. Because IGF-IR is a major factor associated with thickening of mesenteric vessels, our results provide potential therapeutic targets.

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