2. Academic Validation
  3. 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

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

  • J Biol Chem. 2013 Aug 30;288(35):25414-25427. doi: 10.1074/jbc.M113.460287.
Kang Kang 1,  Xiao Peng 1,  Xiaoying Zhang 1,  Yuna Wang 1,  Lishu Zhang 2,  Li Gao 2,  Tingting Weng 2,  Honghao Zhang 2,  Ramaswamy Ramchandran 3,  J Usha Raj 3,  Deming Gou 4,  Lin Liu 5
Affiliations

Affiliations

  • 1 From the College of Life Sciences, Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen University, Shenzhen, Guangdong 518060, China.
  • 2 the Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma 74078, and.
  • 3 the Department of Pediatrics, University of Illinois, Chicago, Illinois 60612.
  • 4 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.
  • 5 the Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma 74078, and. Electronic address: lin.liu@okstate.edu.
PMID: 23853098 DOI: 10.1074/jbc.M113.460287
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.

Keywords

Gene Regulation; High Throughput Screening (HTS); Immunosuppressor; MicroRNA; NFAT Transcription Factor; Pulmonary Hypertension.

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