Angiotensin II induction of PDGF-C expression is mediated by AT1 receptor-dependent Egr-1 transactivation

Platelet-derived growth factors are a family of mitogens and chemoattractants comprising of four ligand genes (A-, B-, C-, D-chains) implicated in many physiologic and pathophysiologic processes, including atherosclerosis, fibrosis and tumorigenesis. Our understanding of the molecular mechanisms, wh...

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Bibliographic Details
Published in:Nucleic acids research 2008-04, Vol.36 (6), p.1941-1951
Main Authors: Sanchez-Guerrero, Estella, Midgley, Valerie C, Khachigian, Levon M
Format: Article
Language:English
Subjects:
Angiotensin II - pharmacology
Animals
Base Sequence
Binding Sites
Cells, Cultured
Early Growth Response Protein 1 - metabolism
Gene Expression
Lymphokines - biosynthesis
Lymphokines - genetics
Molecular Biology
Molecular Sequence Data
Muscle, Smooth, Vascular - cytology
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - metabolism
Platelet-Derived Growth Factor - biosynthesis
Platelet-Derived Growth Factor - genetics
Promoter Regions, Genetic
Rats
Receptor, Angiotensin, Type 1 - metabolism
Transcriptional Activation
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Summary:Platelet-derived growth factors are a family of mitogens and chemoattractants comprising of four ligand genes (A-, B-, C-, D-chains) implicated in many physiologic and pathophysiologic processes, including atherosclerosis, fibrosis and tumorigenesis. Our understanding of the molecular mechanisms, which regulate PDGF-C transcription remains incomplete. Transient transfection analysis, conventional and quantitative real-time PCR revealed the induction of PDGF-C transcription and mRNA expression in smooth muscle cells (SMCs) exposed to the peptide hormone angiotensin (ATII), which induces Egr-1. Occupancy of a G + C-rich element in the proximal region of the PDGF-C promoter was unaffected by ATII. Instead we discovered, using both nuclear extracts and recombinant proteins with EMSA and ChIP analyses, the existence of a second Egr-1-binding element located 500 bp upstream. ATII induction of PDGF-C transcription is mediated by the angiotensin type 1 receptor (AT1R) and Egr-1 activation through this upstream element. DNAzyme ED5 targeting Egr-1 blocked ATII-inducible PDGF-C expression. Moreover, increased PDGF-C expression after exposure to ATII depends upon the differentiation state of the SMCs. This study demonstrates the existence of this novel ATII-AT1R-Egr-1-PDGF-C axis in SMCs of neonatal origin, but not in adult SMCs, where ATII induces Egr-1 but not PDGF-C.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkm923