Vascular peroxidase 1 mediates hypoxia-induced pulmonary artery smooth muscle cell proliferation, apoptosis resistance and migration

Cardiovasc Res. 2018 Jan 1;114(1):188-199. doi: 10.1093/cvr/cvx234.

Abstract

Aims: Reactive oxygen species (ROS) play essential roles in the pulmonary vascular remodelling associated with hypoxia-induced pulmonary hypertension (PH). Vascular peroxidase 1 (VPO1) is a newly identified haeme-containing peroxidase that accelerates oxidative stress development in the vasculature. This study aimed to determine the potential role of VPO1 in hypoxia-induced PH-related vascular remodelling.

Methods and results: The vascular morphology and VPO1 expression were assessed in the pulmonary arteries of Sprague-Dawley (SD) rats. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) and VPO1 expression and HOCl production were significantly increased in hypoxic rats, which also exhibited obvious vascular remodelling. Furthermore, a hypoxia-induced PH model was generated by exposing primary rat pulmonary artery smooth muscle cells (PASMCs) to hypoxic conditions (3% O2, 48 h), which significantly increased the expression of NOX4 and VPO1 and the production of HOCl. These hypoxic changes were accompanied by enhanced proliferation, apoptosis resistance, and migration. In PASMCs, hypoxia-induced changes, including effects on the expression of cell cycle regulators (cyclin B1 and cyclin D1), apoptosis-related proteins (bax, bcl-2, and cleaved caspase-3), migration promoters (matrix metalloproteinases 2 and 9), and NF-κB expression, as well as the production of HOCl, were all inhibited by silencing VPO1 with small interfering RNAs. Moreover, treatment with HOCl under hypoxic conditions upregulated NF-κB expression and enhanced proliferation, apoptosis resistance, and migration in PASMCs, whereas BAY 11-7082 (an inhibitor of NF-κB) significantly inhibited these effects.

Conclusion: Collectively, these results demonstrate that VPO1 promotes hypoxia-induced proliferation, apoptosis resistance, and migration in PASMCs via the NOX4/VPO1/HOCl/NF-κB signalling pathway.

Keywords: Hypoxia; NF-κB; Pulmonary artery smooth muscle cells; Pulmonary vascular remodelling; Vascular peroxidase 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis*
  • Cell Cycle Proteins / metabolism
  • Cell Hypoxia
  • Cell Movement*
  • Cell Proliferation*
  • Cells, Cultured
  • Disease Models, Animal
  • Hemeproteins / metabolism*
  • Hypertension, Pulmonary / enzymology*
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / pathology
  • Hypochlorous Acid / metabolism
  • Hypoxia / complications*
  • Hypoxia / enzymology
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Muscle, Smooth, Vascular / enzymology*
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / enzymology*
  • Myocytes, Smooth Muscle / pathology
  • NADPH Oxidase 4 / metabolism
  • NF-kappa B / metabolism
  • Peroxidases / metabolism*
  • Pulmonary Artery / enzymology
  • Pulmonary Artery / pathology
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Vascular Remodeling*

Substances

  • Apoptosis Regulatory Proteins
  • Cell Cycle Proteins
  • Hemeproteins
  • NF-kappa B
  • Hypochlorous Acid
  • vascular peroxidase, rat
  • Peroxidases
  • NADPH Oxidase 4
  • Nox4 protein, rat
  • Matrix Metalloproteinase 2
  • Mmp2 protein, rat
  • Matrix Metalloproteinase 9
  • Mmp9 protein, rat