Angiotensin II Stimulates Transcription of Insulin-like Growth Factor 1 Receptor in Vascular Smooth Muscle Cells: Role of NF-B

Ma Y, Zhang L, Peng T, Cheng J, Taneja S, Zhang J, Delafontaine P and Du J
Source: Endocrinology
Publication Date: (2006)
Issue: 147(3): 1256-63
Research Area:
Cells used in publication:
Aortic Smooth Muscle Cells (R-ASM), Rat
Species: rat
Tissue Origin: aortic
Increased expression of the insulin-like growth factor 1 receptor (IGF-1R) 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-1R. Now, we show that mesenteric arteries of rats infused with Ang II develop thickening and increased IGF-1R expression. To determine how Ang II transcriptionally regulates IGF-1R expression in VSMCs, we generated 5'-end deletions of the IGF-1R 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 to -135 of the IGF-1R promoter. Using a DNase I foot printing analysis we identified two putative "NF-kappaB-like" sequences located in the same region of the IGF-1R promoter. When we mutated either of these NF-kappaB-like sites, Ang II-induced IGF-1R 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-1R promoter. When we blocked the Ras/MEK1 pathway or the IKK pathway, both Ang II-induced IGF-1R promoter activity and expression of IGF-1R protein significantly declined. Our results indicate that the mechanism by which Ang II stimulates IGF-1R expression in VSMCs involves NF-kappaB binding to NF-kappaB sites in the IGF-1R promoter, leading to expression of IGF-1R through both Ras/MEK1-and IKK-dependent pathways. Since IGF-1R is a major factor associated with thickening of mesenteric vessels, our results provide potential therapeutic targets.