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Angiotensin II‐regulated Genes in Vascular Smooth Muscle Cells: Promoter Interactions between CREB and HIF
Author(s) -
Lounsbury Karen M.,
Rose Patricia,
Sateriale Adam,
Roy Daniel,
Taggart Laura,
Wellman Theresa
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.585.5
Subject(s) - creb , angiotensin ii , gene knockdown , transcription factor , vascular smooth muscle , cyclic amp response element binding protein , chromatin immunoprecipitation , response element , promoter , biology , downregulation and upregulation , endocrinology , medicine , microbiology and biotechnology , gene expression , gene , genetics , smooth muscle , blood pressure
The underlying cause of genetic changes in vascular smooth muscle from hypertensive disease is uncertain. The transcription factor CREB is hyperactive in cerebral arteries from Dahl S hypertensive rats and is activated by angiotensin II (Ang II) in cultured smooth muscle cells. By using microarray analyses, we identified several CRE‐containing genes that are calcium‐dependent and/or upregulated in arteries from Dahl hypertensive rats. Our objective was to test the hypothesis that Ang II regulates these genes through complex interactions between CREB and other transcription factors. The MAP kinase phosphatase‐1 (mkp‐1) gene was chosen for analysis due to its induction by Ang II and its role in cell proliferation. Analysis of the mkp‐1 promoter revealed nucleotide overlap between its CRE sites and hypoxia response elements (HREs). Ang II promoted specific interaction between CREB and an mkp‐1 CRE/HIF promoter region, as measured by chromatin immunoprecipitation (ChIP). Knockdown of CREB using siRNA also prevented induction of mkp‐1 mRNA levels by Ang II. Hypoxic induction of HIF‐1α blunted the Ang II induction of mkp‐1 transcription, and reduced mRNA levels of CREB, suggesting that HIF‐1α may inhibit CREB‐mediated transcription. These results provide new evidence for hypoxic regulation of Ang II‐mediated gene expression. Supported by NIH HL067351 and the Totman Center for Cerebrovascular Research.