title: MicroRNA-124 suppresses the transactivation of nuclear factor of activated T cells by targeting multiple genes and inhibits the proliferation of pulmonary artery smooth muscle cells.
abstract: Abnormal proliferation and phenotypic modulation of pulmonary artery smooth muscle cells (PASMC) contributes to the pathogenesis of numerous cardiovascular disorders, including pulmonary arterial hypertension (PAH). The nuclear factor of activated T cells (NFAT) signaling pathway is linked to PASMC proliferation and PAH. MicroRNAs (miRNAs) are small non-coding RNAs that function in diverse biological processes. To systemically identify the specific miRNAs that regulate the NFAT pathway, a human primary miRNA library was applied for cell-based high throughput screening with the NFAT luciferase reporter system. Eight miRNAs were found to modulate NFAT activity efficiently. Of them, miR-124 robustly inhibited NFAT reporter activity and decreased both the dephosphorylation and the nuclear translocation of NFAT. miR-124 also inhibited NFAT-dependent transcription of IL-2 in Jurkat T cells. miR-124 exerted its effects by targeting multiple genes, including a known component of the NFAT pathway, NFATc1, and two new regulators of NFAT signaling, CAMTA1 (calmodulin-binding transcription activator 1) and PTBP1 (polypyrimidine tract-binding protein 1). Physiologically, miR-124 was down-regulated by hypoxia in human PASMC, consistent with the activation of NFAT during this process. Down-regulation of miR-124 was also observed in 3-week hypoxia-treated mouse lungs. Furthermore, the overexpression of miR-124 not only inhibited human PASMC proliferation but also maintained its differentiated phenotype by repressing the NFAT pathway. Taken together, our data provide the first evidence that miR-124 acts as an inhibitor of the NFAT pathway. Down-regulation of miR-124 in hypoxia-treated PASMC and its antiproliferative and prodifferentiation effects imply a potential value for miR-124 in the treatment of PAH.
authors.affiliation: From the College of Life Sciences, Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen University, Shenzhen, Guangdong 518060, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Kang
authors.affiliation: From the College of Life Sciences, Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen University, Shenzhen, Guangdong 518060, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Peng
authors.affiliation: From the College of Life Sciences, Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen University, Shenzhen, Guangdong 518060, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the College of Life Sciences, Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen University, Shenzhen, Guangdong 518060, China.
authors.forename: Yuna
authors.initials: Y
authors.lastname: Wang
authors.affiliation: the Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma 74078, and.
authors.forename: Lishu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: the Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma 74078, and.
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.affiliation: the Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma 74078, and.
authors.forename: Tingting
authors.initials: T
authors.lastname: Weng
authors.affiliation: the Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma 74078, and.
authors.forename: Honghao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: the Department of Pediatrics, University of Illinois, Chicago, Illinois 60612.
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Ramchandran
authors.affiliation: the Department of Pediatrics, University of Illinois, Chicago, Illinois 60612.
authors.forename: J Usha
authors.initials: JU
authors.lastname: Raj
authors.affiliation: From the College of Life Sciences, Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen University, Shenzhen, Guangdong 518060, China,; the Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma 74078, and; the Department of Pediatrics, University of Illinois, Chicago, Illinois 60612. Electronic address: dmgou@szu.edu.cn.
authors.forename: Deming
authors.initials: D
authors.lastname: Gou
authors.affiliation: the Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma 74078, and. Electronic address: lin.liu@okstate.edu.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019169:Jurkat Cells; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation
chemical_list: C509207:MIRN124 microRNA, human; D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse; D050778:NFATC Transcription Factors
keywords: Gene Regulation; High Throughput Screening (HTS); Immunosuppressor; MicroRNA; NFAT Transcription Factor; Pulmonary Hypertension