Generation and Analysis of Smooth Muscle-Specific C/EBP-δ Transgenic Rats

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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, PDGF receptor (PDGFR). PDGF α-receptor (PDGFaR) 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 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 here developed C/EBP-δ transgenic rats 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 PBGFs. Targeted overexpression ofC/EBP-δ evokes high levels of PDGFαR gene expression, susceptibility to VSMC growth, and proliferation of VSMCs to PDGFs. The results obtained herein show evidence of a new role and new functional significance of C/EBP-δ on VSMC growth via PDGFαR during the process of vascular remodeling and atherosclerosis.