title: Synthetic retinoid Am80 up-regulates apelin expression by promoting interaction of RARα with KLF5 and Sp1 in vascular smooth muscle cells.
abstract: 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-β 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.
authors.affiliation: *Department of Biochemistry and Molecular Biology, the Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361, Zhongshan East Road, Shijiazhuang, 050017, China.
authors.forename: Xin-Rui
authors.initials: XR
authors.lastname: Lv
authors.forename: Bin
authors.initials: B
authors.lastname: Zheng
authors.forename: Shu-Ya
authors.initials: SY
authors.lastname: Li
authors.forename: Ai-Li
authors.initials: AL
authors.lastname: Han
authors.forename: Chang
authors.initials: C
authors.lastname: Wang
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Shi
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Li
authors.forename: Jin-Kun
authors.initials: JK
authors.lastname: Wen
mesh_terms: D000818:Animals; D000073861:Apelin; D001565:Benzoates / Q000494:pharmacology*; D017536:Carotid Artery, Common / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics; D015854:Up-Regulation; D016335:Zinc Fingers
chemical_list: D000073861:Apelin; C498579:Apln protein, rat; D001565:Benzoates; D036341:Intercellular Signaling Peptides and Proteins; C492215:Klf5 protein, rat; D051741:Kruppel-Like Transcription Factors; C000607073:Rara protein, rat; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D016329:Sp1 Transcription Factor; D013764:Tetrahydronaphthalenes; D016212:Transforming Growth Factor beta; C061133:tamibarotene