Targeted Overexpression of CCAAT/Enhancer-Binding Protein-δ Evokes Enhanced Gene Transcription of Platelet-Derived Growth Factor α-Receptor in Vascular Smooth Muscle Cells

Abstract

Abstract— Platelet-derived growth factor (PDGF) is thought to play a significant role in various models of vascular remodeling, particularly in the early process of vascular diseases. Its action is mediated by its specific receptor, the PDGF receptor. The PDGF α-receptor (PDGFαR) plays an important role in the growth and proliferation of vascular smooth muscle cells (VSMCs), and its gene expression is thought to be regulated by several potential transcriptional nuclear factors. However, the detailed mechanisms of tissue-specific transactivation of the PDGFαR gene in VSMCs remain to be clarified. We have previously demonstrated that the rat PDGFαR gene contains an enhancer core sequence for CCAAT/enhancer-binding proteins (C/EBPs) in its promoter region, and we have also suggested that C/EBP-δ is the principal factor involved in the induction of tissue-specific transcriptional activity of the PDGFαR gene in VSMCs. To explore the definitive roles of C/EBP-δ protein on PDGFαR gene transcription in VSMCs, we developed C/EBP-δ transgenic rats by using a chimeric fusion gene of the mouse smooth muscle α-actin promoter and an entire coding region of rat C/EBP-δ cDNA. This report describes the first successful targeted overexpression of C/EBP-δ capable of inducing PDGFαR gene transcription and modifying cell proliferative activity to PDGFs. Targeted overexpression of C/EBP-δ evokes high levels of PDGFαR gene expression, susceptibility to VSMC growth, and proliferation of VSMCs to PDGFs. The results obtained reveal evidence of a new role and new functional significance of C/EBP-δ on VSMC growth via the PDGFαR during the process of vascular remodeling and atherosclerosis.