MiR-17/20 controls prolyl hydroxylase 2 (PHD2)/hypoxia-inducible factor 1 (HIF1) to regulate pulmonary artery smooth muscle cell proliferation

Tianji Chen, Qiyuan Zhou, Haiyang Tang, Melike Bozkanat, Jason X.J. Yuan, J. Usha Raj, Guofei Zhou

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Background-Previously we found that smooth muscle cell (SMC)-specific knockout of miR-17~92 attenuates hypoxia-induced pulmonary hypertension. However, the mechanism underlying miR-17~92-mediated pulmonary artery SMC (PASMC) proliferation remains unclear. We sought to investigate whether miR-17~92 regulates hypoxia-inducible factor (HIF) activity and PASMC proliferation via prolyl hydroxylases (PHDs). Methods and Results-We show that hypoxic sm-17~92-/- mice have decreased hematocrit, red blood cell counts, and hemoglobin contents. The sm-17~92-/- mouse lungs express decreased mRNA levels of HIF targets and increased levels of PHD2. miR-17~92 inhibitors suppress hypoxia-induced levels of HIF1α, VEGF, Glut1, HK2, and PDK1 but not HIF2a in vitro in PASMC. Overexpression of miR-17 in PASMC represses PHD2 expression, whereas miR-17/20a inhibitors induce PHD2 expression. The 30-UTR of PHD2 contains a functional miR-17/20a seed sequence. Silencing of PHD2 induces HIF1α and PCNA protein levels, whereas overexpression of PHD2 decreases HIF1α and cell proliferation. SMC-specific knockout of PHD2 enhances hypoxia-induced vascular remodeling and exacerbates established pulmonary hypertension in mice. PHD2 activator R59949 reverses vessel remodeling in existing hypertensive mice. PHDs are dysregulated in PASMC isolated from pulmonary arterial hypertension patients. Conclusions-Our results suggest that PHD2 is a direct target of miR-17/20a and that miR-17~92 contributes to PASMC proliferation and polycythemia by suppression of PHD2 and induction of HIF1α.

Original languageEnglish (US)
Article numbere004510
JournalJournal of the American Heart Association
Volume5
Issue number12
DOIs
StatePublished - Jan 1 2016

Keywords

  • Hypoxia
  • Hypoxia-inducible factor 1
  • MiR-17~92
  • Prolyl hydroxylase 2
  • Pulmonary artery smooth muscle cell
  • Pulmonary hypertension
  • Pulmonary hypertension
  • Smooth muscle cell

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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