A High Level of CCAAT-Enhancer Binding Protein-δ Expression Is a Major Determinant for Markedly Elevated Differential Gene Expression of the Platelet-Derived Growth Factor-α Receptor in Vascular Smooth Muscle Cells of Genetically Hypertensive Rats

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Abstract
—Platelet-derived growth factor-α receptor (PDGF-αR) 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-αR or its transcription-regulating mechanisms or factors are significantly related to genetic hypertension. To evaluate the role of PDGF-αR 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-αR 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-αR gene transcription. DNA-protein binding studies by competition in electromobility shift and supershift assays revealed that 2 members, C/EBP-β and C/EBP-δ, are mainly responsible for DNA-protein complex formation; the former acts as a transcriptional repressor and the latter as an activator of the PDGF-αR gene, respectively. Western or Northern blot analyses supported evidence for high expression of C/EBP-δ seen only in SHR-derived VSMCs. Furthermore, forced expression of C/EBP-δ transactivated the transcriptional efficiency of the PDGF-αR gene even in WKY-derived VSMCs, whereas that of C/EBP-β had an opposite effect in SHR-derived VSMCs. These findings indicate that differential expression of members of the C/EBP family, mainly C/EBP-δ and possibly C/EBP-β, are responsible for the strain-specific gene transcription of PDGF-αR in VSMCs.