Growth Factor Midkine Aggravates Pulmonary Arterial Hypertension via Surface Nucleolin

Sci Rep. 2020 Jun 25;10(1):10345. doi: 10.1038/s41598-020-67217-w.

Abstract

Pulmonary arterial hypertension (PAH) is a progressive fatal disease caused by pulmonary arterial remodeling. Midkine regulates cell proliferation and migration, and it is induced by hypoxia, but its roles in pulmonary arterial remodeling remain unclear. Serum midkine levels were significantly increased in PAH patients compared with control patients. Midkine expression was increased in lungs and sera of hypoxia-induced PAH mice. Hypoxia-induced pulmonary arterial remodeling and right ventricular hypertrophy were attenuated in midkine-knockout mice. Midkine-induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMC) and epidermal growth factor receptor (EGFR) signaling were significantly increased under hypoxia, which also induced cell-surface translocation of nucleolin. Nucleolin siRNA treatment suppressed midkine-induced EGFR activation in vitro, and nucleolin inhibitor AS1411 suppressed proliferation and migration of PASMC induced by midkine. Furthermore, AS1411 significantly prevented the development of PAH in Sugen hypoxia rat model. Midkine plays a crucial role in PAH development through interaction with surface nucleolin. These data define a role for midkine in PAH development and suggest midkine-nucleolin-EGFR axis as a novel therapeutic target for PAH.

MeSH terms

  • Aged
  • Animals
  • Cell Membrane / metabolism
  • Cell Movement / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Disease Models, Animal
  • ErbB Receptors / metabolism
  • Female
  • Humans
  • Hypoxia / complications*
  • Hypoxia / physiopathology
  • Lung / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Midkine / blood
  • Midkine / genetics
  • Midkine / metabolism*
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / pathology
  • Oligodeoxyribonucleotides / pharmacology
  • Oligodeoxyribonucleotides / therapeutic use
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / metabolism*
  • Primary Cell Culture
  • Pulmonary Arterial Hypertension / blood
  • Pulmonary Arterial Hypertension / pathology*
  • Pulmonary Arterial Hypertension / prevention & control
  • Pulmonary Artery / cytology
  • Pulmonary Artery / pathology
  • RNA-Binding Proteins / antagonists & inhibitors
  • RNA-Binding Proteins / metabolism*
  • Rats
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Vascular Remodeling / physiology*

Substances

  • AGRO 100
  • MDK protein, human
  • Mdk protein, mouse
  • Mdk protein, rat
  • Oligodeoxyribonucleotides
  • Phosphoproteins
  • RNA-Binding Proteins
  • nucleolin
  • Midkine
  • EGFR protein, human
  • EGFR protein, mouse
  • ErbB Receptors