miR-92b-3p-TSC1 axis is critical for mTOR signaling-mediated vascular smooth muscle cell proliferation induced by hypoxia

Cell Death Differ. 2019 Sep;26(9):1782-1795. doi: 10.1038/s41418-018-0243-z. Epub 2018 Dec 5.

Abstract

Pulmonary artery smooth muscle cells (PASMCs) undergo proliferation by the mammalian target of rapamycin (mTOR) signaling pathway under hypoxia. Hypoxia induces expression of a specific set of microRNAs (miRNAs) in a variety of cell types. We integrated genomic analyses of both small non-coding RNA and coding transcripts using next-generation sequencing (NGS)-based RNA sequencing with the molecular mechanism of the mTOR signaling pathway in hypoxic PASMCs. These analyses revealed hypoxia-induced miR-92b-3p as a potent regulator of the mTOR signaling pathway. We demonstrated that miR-92b-3p directly targets the 3'-UTR of a negative regulator in the mTOR signaling pathway, TSC1. mTOR signaling and consequent cell proliferation were promoted by enforced expression of miR-92b-3p but inhibited by knocking down endogenous miR-92b-3p. Furthermore, inhibition of miR-92b-3p attenuated hypoxia-induced proliferation of vascular smooth muscle cells (VSMCs). Therefore, this study elucidates a novel role of miR-92b-3p as a hypoxamir in the regulation of the mTOR signaling pathway and the pathological VSMC proliferative response under hypoxia. These findings will help us better understand the miRNA-mediated molecular mechanism of the proliferative response of hypoxic VSMCs through the mTOR signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Hypoxia / genetics*
  • Cell Proliferation / genetics
  • Gene Expression Regulation / genetics
  • High-Throughput Nucleotide Sequencing
  • Humans
  • MicroRNAs / genetics*
  • Myocytes, Smooth Muscle / metabolism
  • Pulmonary Artery / growth & development
  • Pulmonary Artery / metabolism
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / genetics*
  • Tuberous Sclerosis Complex 1 Protein / genetics*

Substances

  • MIRN92 microRNA, human
  • MicroRNAs
  • TSC1 protein, human
  • Tuberous Sclerosis Complex 1 Protein
  • TOR Serine-Threonine Kinases