Modulation of Pulmonary Vascular Remodeling in Hypoxia: Role of 15-LOX-2/15-HETE-MAPKs Pathway

Cell Physiol Biochem. 2015;35(6):2079-97. doi: 10.1159/000374015. Epub 2015 Apr 7.


Background: We have previously shown that 15-hydroxyeicosatetraenoic acid (15-HETE) plays a critical role in pulmonary hypertension (PH)-associated vascular remodeling. However, the signaling mechanisms remain unclear. The purpose of this study was to investigate the role of 15-lipoxygenase-2 (15-LO-2)/15-HETE-mitogen-activated protein kinases (MAPKs) pathway in hypoxia-induced pulmonary vascular remodeling and the underlying mechanisms.

Methods: The arterial wall thickness was measured by hematoxylin and eosin (HE) staining in distal pulmonary arteries isolated from normal and PAH patient-derived lungs. The protein expression of phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated p38 mitogen-activated protein kinases (p-p38MAPK) were measured by Western blot in the lungs of PAH patients and hypoxia-induced rats. The apoptosis of cultured rat pulmonary arterial smooth muscle cells (PASMCs) was determined by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Flow cytometry. The cell proliferation and cell cycle in PASMCs following hypoxia were analyzed by bromodeoxyuridine incorporation and flow cytometry, respectively.

Results: Our results showed that the levels of p-ERK and p-p38MAPK were both drastically elevated in lungs from human patients and hypoxic rats. The HE staining revealed that the medial wall thickness was higher in patients with PAH than normal humans. In cultured PASMCs, Hypoxia stimulated the cell proliferation, the cell cycle progression, and subsequently promoted cell differentiation and cell migration leading to the suppressed cell apoptosis. Furthermore, MAPKs- induced cell proliferation and anti-apoptosis in PASMCs is 15-LO-2/15HETE activation-dependent.

Conclusion: Our study indicates that hypoxia-induced pulmonary vascular remodeling is associated with increased levels of 15-LO-2 and 15-HETE. 15-LO-2/15-HETE stimulates the cell proliferation and anti-apoptosis in PASMCs through phosphorylation of ERK and p38MAPK, which subsequently contributing to hypoxia-induced pulmonary vascular remodeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Apoptosis / physiology
  • Arachidonate 15-Lipoxygenase / metabolism*
  • Cell Cycle / physiology
  • Cell Differentiation / physiology
  • Cell Movement / physiology
  • Cell Proliferation / physiology
  • Cells, Cultured
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Humans
  • Hydroxyeicosatetraenoic Acids / metabolism*
  • Hypoxia / metabolism
  • Hypoxia / physiopathology*
  • Lung / metabolism
  • Lung / physiology*
  • Male
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / physiology
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / physiology
  • Pulmonary Artery / metabolism
  • Pulmonary Artery / physiology*
  • Rats
  • Signal Transduction / physiology
  • Vascular Remodeling / physiology*
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Hydroxyeicosatetraenoic Acids
  • 15-hydroxy-5,8,11,13-eicosatetraenoic acid
  • ALOX15B protein, human
  • Arachidonate 15-Lipoxygenase
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases