Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin αvβ3/FAK/AKT Pathway Suppression

Circ Cardiovasc Genet. 2017 Feb;10(1):e001591. doi: 10.1161/CIRCGENETICS.116.001591.

Abstract

Background: Pulmonary arterial remodeling characterized by increased vascular smooth muscle proliferation is commonly seen in life-threatening disease, pulmonary arterial hypertension (PAH). Clinical studies have suggested a correlation between osteoprotegerin serum levels and PAH severity. Here, we aimed to invhestigate vascular osteoprotegerin expression and its effects on pulmonary arterial smooth muscle cell proliferation in vitro and in vivo, as well as examine the signal transduction pathways mediating its activity.

Methods and results: Serum osteoprotegerin levels were significantly elevated in patients with PAH and correlated with disease severity as determined by the World Health Organization (WHO) functional classifications and 6-minute walking distance tests. Similarly, increased osteoprotegerin expression was observed in the pulmonary arteries of hypoxia plus SU5416- and monocrotaline-induced PAH animal models. Moreover, osteoprotegerin disruption attenuated hypoxia plus SU5416-induced PAH progression by reducing pulmonary vascular remodeling, whereas lentiviral osteoprotegerin reconstitution exacerbated PAH by increasing pulmonary arterial smooth muscle cell proliferation. Furthermore, pathway analysis revealed that osteoprotegerin induced pulmonary arterial smooth muscle cell proliferation by interacting with integrin αvβ3 to elicit downstream focal adhesion kinase and AKT pathway activation.

Conclusions: Osteoprotegerin facilitates PAH pathogenesis by regulating pulmonary arterial smooth muscle cell proliferation, suggesting that it may be a potential biomarker and therapeutic target in this disease.

Keywords: biomarkers; cell proliferation; osteoprotegerin; pulmonary hypertension; pulmonary vascular smooth muscle cells.

MeSH terms

  • Animals
  • Arterial Pressure*
  • Case-Control Studies
  • Cell Proliferation
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Focal Adhesion Kinase 1 / genetics
  • Focal Adhesion Kinase 1 / metabolism*
  • Humans
  • Hypertension, Pulmonary / chemically induced
  • Hypertension, Pulmonary / enzymology
  • Hypertension, Pulmonary / physiopathology
  • Hypertension, Pulmonary / prevention & control*
  • Hypoxia / complications*
  • Indoles*
  • Integrin alphaVbeta3 / genetics
  • Integrin alphaVbeta3 / metabolism
  • Male
  • Mice, Knockout
  • Middle Aged
  • Monocrotaline
  • Muscle, Smooth, Vascular / enzymology*
  • Muscle, Smooth, Vascular / physiopathology
  • Osteoprotegerin / blood
  • Osteoprotegerin / deficiency
  • Osteoprotegerin / genetics
  • Osteoprotegerin / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pulmonary Artery / enzymology
  • Pulmonary Artery / physiopathology
  • Pyrroles*
  • RNA Interference
  • Rats, Sprague-Dawley
  • Severity of Illness Index
  • Signal Transduction*
  • Transfection
  • Vascular Remodeling
  • Walk Test

Substances

  • Indoles
  • Integrin alphaVbeta3
  • Osteoprotegerin
  • Pyrroles
  • TNFRSF11B protein, human
  • Tnfrsf11b protein, mouse
  • Semaxinib
  • Monocrotaline
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • Ptk2 protein, mouse
  • Proto-Oncogene Proteins c-akt