© 1999 American Heart Association, Inc.
Original Contribution |
A High Level of CCAAT-Enhancer Binding Protein-
Expression Is a Major Determinant for Markedly Elevated Differential Gene Expression of the Platelet-Derived Growth Factor-
Receptor in Vascular Smooth Muscle Cells of Genetically Hypertensive Rats
From the Second Department of Internal Medicine (Y.K., T.F., K.H.), Ehime University School of Medicine, Onsen-gun, Ehime, Japan, and Departments of Biochemistry and Medicine (T.I.), Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Yutaka Kitami, MD, Second Department of Internal Medicine, Ehime University School of Medicine, Onsen-gun, Ehime 791-0295, Japan. E-mail kitamiyk{at}m.ehime-u.ac.jp
Abstract—Platelet-derived
growth factor-
receptor (PDGF-R) expression is markedly elevated
in cultured vascular smooth muscle cells (VSMCs) from spontaneously
hypertensive rats (SHR) when compared with normotensive rat strains,
Sprague-Dawley, Wistar, and Wistar-Kyoto rats (WKY). This
"almost-all-or-none" type of differential expression strongly
suggests that PDGF-R or its transcription-regulating mechanisms or
factors are significantly related to genetic hypertension. To evaluate
the role of PDGF-R in vascular remodeling and hypertension, we have
investigated the underlying molecular mechanism. We have recently shown
that the regulatory domain responsible for this difference is localized
to the PDGF-R promoter region between –246 and –139, which
contains an enhancer core sequence specific for CCAAT-enhancer binding
proteins (C/EBPs). We defined the roles of this element for
hypertensive strain-specific PDGF-R gene transcription. DNA-protein
binding studies by competition in electromobility shift and supershift
assays revealed that 2 members, C/EBP-ß and C/EBP-
, are mainly
responsible for DNA-protein complex formation; the former acts as a
transcriptional repressor and the latter as an activator of
the PDGF-R gene, respectively. Western or Northern blot
analyses supported evidence for high expression of C/EBP-
seen only in SHR-derived VSMCs. Furthermore, forced expression of
C/EBP- transactivated the transcriptional efficiency of the
PDGF-R gene even in WKY-derived VSMCs, whereas that of C/EBP-ß had
an opposite effect in SHR-derived VSMCs. These findings indicate that
differential expression of members of the C/EBP family, mainly
C/EBP- and possibly C/EBP-ß, are responsible for the
strain-specific gene transcription of PDGF-R in VSMCs.
Key Words: platelet-derived growth factor -receptor • vascular smooth muscle cell • promoter activity • strain-specific gene transcription • CCAAT-enhancer binding protein
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