AntagomiR-451 inhibits oxygen glucose deprivation (OGD)-induced HUVEC necrosis via activating AMPK signaling

PLoS One. 2017 Apr 26;12(4):e0175507. doi: 10.1371/journal.pone.0175507. eCollection 2017.

Abstract

Oxygen glucose deprivation (OGD) application in cultured human umbilical vein endothelial cells (HUVECs) mimics ischemic injuries. AntagomiR-451, the miroRNA-451 ("miR-451") inhibitor, could activate pro-survival AMP-activated protein kinase (AMPK) signaling. In the current study, we showed that forced-expression of antagomiR-451 depleted miRNA-451 and significantly attenuated OGD-induced necrosis of HUVECs. Activation of AMPK was required for antagomiR-451-mediated pro-survival actions. AMPK inhibition, by AMPKα shRNA or dominant negative mutation, almost completely abolishedantagomiR-451-mediated HUVEC protection again OGD. Reversely, forced-activation of AMPK by exogenous expression of constructively-active AMPKα inhibited OGD-induced HUVEC necrosis. At the molecular level, antagomiR-451 expression in HUVECs inhibited OGD-induced programmed necrosis, the latter was evidenced by mitochondrial p53-cyclophilinD (Cyp-D) association, mitochondrial depolarization as well as reactive oxygen species (ROS) production and lactate dehydrogenase (LDH) breach. Together, we suggest that antagomiR-451 activates AMPK to inhibit OGD-induced programmed necrosis in HUVECs.

MeSH terms

  • AMP-Activated Protein Kinases / antagonists & inhibitors
  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Antagomirs / metabolism*
  • Cell Survival
  • Cyclophilins / metabolism
  • Glucose / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Mitochondria / metabolism
  • Necrosis
  • Oxygen / metabolism
  • Peptidyl-Prolyl Isomerase F
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antagomirs
  • Peptidyl-Prolyl Isomerase F
  • MIRN451 microRNA, human
  • MicroRNAs
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53
  • AMP-Activated Protein Kinases
  • Cyclophilins
  • Glucose
  • Oxygen

Grants and funding

This study was supported by the military logistics research project and research program (AWS14C003, to Yong-Qing Xu). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.