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Endocrinology. 2006 Mar;147(3):1256-63. Epub 2005 Dec 1.

Angiotensin II stimulates transcription of insulin-like growth factor I receptor in vascular smooth muscle cells: role of nuclear factor-kappaB.

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  • 1Department of Medicine, One Baylor Plaza, N520, Baylor College of Medicine, Houston, Texas 77030, USA.


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-kappaB (NF-kappaB)-like sequences located in the same region of the IGF-IR promoter. When we mutated either of these NF-kappaB-like sites, Ang II-induced IGF-IR promoter activity decreased sharply. Electrophoretic mobility gel shift, anti-p50 of NF-kappaB supershift and chromatin immunoprecipitation assays demonstrated that both the p65 and p50 subunits of NF-kappaB 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-kappaB 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-kappaB binding to NF-kappaB sites in the IGF-IR promoter, leading to expression of IGF-IR through both Ras/MAPK kinase 1-and inhibitory-kappaB 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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