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

Platelet-derived growth factor-a receptor (PDGF-aR) 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-aR or its transcription-regulating mechanisms or factors are significantly related to genetic hypertension. To evaluate the role of PDGF-aR 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-aR 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-aR gene transcription. DNA-protein binding studies by competition in electromobility shift and supershift assays revealed that 2 members, C/EBP-b and C/EBP-d, are mainly responsible for DNA-protein complex formation; the former acts as a transcriptional repressor and the latter as an activator of the PDGF-aR gene, respectively. Western or Northern blot analyses supported evidence for high expression of C/EBP-d seen only in SHR-derived VSMCs. Furthermore, forced expression of C/EBP-d transactivated the transcriptional efficiency of the PDGF-aR gene even in WKY-derived VSMCs, whereas that of C/EBP-b had an opposite effect in SHR-derived VSMCs. These findings indicate that differential expression of members of the C/EBP family, mainly C/EBP-d and possibly C/EBP-b, are responsible for the strain-specific gene transcription of PDGF-aR in VSMCs. (Circ Res. 1999;84:64-73.)