RESUMO
Previous studies have demonstrated that both retinoids and apelin possess potent cardiovascular properties and that retinoids can mediate the expression of many genes in the cardiovascular system. However, it is not clear whether and how retinoids regulate apelin expression in rat VSMCs (vascular smooth muscle cells). In the present study, we investigated the molecular mechanism of apelin expression regulation by the synthetic retinoid Am80 in VSMCs. The results showed that Am80 markedly up-regulated apelin mRNA and protein levels in VSMCs. Furthermore, KLF5 (Krüppel-like factor 5) and Sp1 (stimulating protein-1) co-operatively mediated Am80-induced apelin expression through their direct binding to the TCE (transforming growth factor-ß control element) on the apelin promoter. Interestingly, upon Am80 stimulation, the RARα (retinoic acid receptor α) was recruited to the apelin promoter by interacting with KLF5 and Sp1 prebound to the TCE site of the apelin promoter to form a transcriptional activation complex, subsequently leading to the up-regulation of apelin expression in VSMCs. An in vivo study indicated that Am80 increased apelin expression in balloon-injured arteries of rats, consistent with the results from the cultured VSMCs. Thus the results of the present study describe a novel mechanism of apelin regulation by Am80 and further expand the network of RARα in the retinoid pathway.
Assuntos
Benzoatos/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Fatores de Transcrição Kruppel-Like/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Receptores do Ácido Retinoico/metabolismo , Fator de Transcrição Sp1/metabolismo , Tetra-Hidronaftalenos/farmacologia , Animais , Apelina , Artéria Carótida Primitiva/efeitos dos fármacos , Artéria Carótida Primitiva/metabolismo , Artéria Carótida Primitiva/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Regiões Promotoras Genéticas , Ratos , Ratos Sprague-Dawley , Receptores do Ácido Retinoico/agonistas , Receptor alfa de Ácido Retinoico , Transdução de Sinais , Transcrição Gênica , Fator de Crescimento Transformador beta/genética , Regulação para Cima , Dedos de ZincoRESUMO
Abnormal proliferation of vascular smooth muscle cells (VSMCs) is a key event in atherosclerosis and restenosis. In this paper, we report that Y-box binding protein 1 (YB1) functions as a phenotypic regulator in VSMC proliferation-differentiation switching through targeting GC box-dependent genes. Oligo pull-down assays demonstrated that YB1 binds directly to GC boxes via amino acids 125-220. YB1 C-terminal tail domain (CTD, amino acids 125-324) regulates GC box-dependent target gene transcription and suppresses VSMC proliferation. These findings provide a novel insight into the regulation of GC box-related genes by YB1, and provide a new understanding of VSMC proliferation regulation.
