Reciprocal regulation of Rac1 and PAK-1 by HIF-1alpha: a positive-feedback loop promoting pulmonary vascular remodeling

Antioxid Redox Signal. 2010 Aug 15;13(4):399-412. doi: 10.1089/ars.2009.3013.

Abstract

Pulmonary vascular remodeling associated with pulmonary hypertension is characterized by media thickening, disordered proliferation, and in situ thrombosis. The p21-activated kinase-1 (PAK-1) can control growth, migration, and prothrombotic activity, and the hypoxia-inducible transcription factor HIF-1alpha was associated with pulmonary vascular remodeling. Here we studied whether PAK-1 and HIF-1alpha are linked in pulmonary vascular remodeling. PAK-1 was expressed in the media of remodeled pulmonary vessels from patients with pulmonary vasculopathy and was upregulated, together with its upstream regulator Rac1 and HIF-1alpha in lung tissue from lambs with pulmonary vascular remodeling. PAK-1 and Rac1 were activated by thrombin involving calcium, thus resulting in enhanced generation of reactive oxygen species (ROS) in human pulmonary artery smooth muscle cells (PASMCs). Activation of PAK-1 stimulated HIF activity and HIF-1alpha expression involving ROS and NF-kappaB, enhanced the expression of the HIF-1 target gene plasminogen activator inhibitor-1, and stimulated PASMC proliferation. Importantly, HIF-1 itself bound to the Rac1 promoter and enhanced Rac1 and PAK-1 transcription. Thus, PAK-1 and its activator Rac1 are novel HIF-1 targets that may constitute a positive-feedback loop for induction of HIF-1alpha by thrombin and ROS, thus explaining elevated levels of PAK-1, Rac1, and HIF-1alpha in remodeled pulmonary vessels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Calcium / metabolism
  • Cell Line
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Enzyme Activation / drug effects
  • Female
  • Hep G2 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Immunohistochemistry
  • In Vitro Techniques
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Pregnancy
  • Pulmonary Artery / metabolism*
  • Pulmonary Artery / pathology
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sheep
  • Thrombin / pharmacology
  • p21-Activated Kinases / genetics
  • p21-Activated Kinases / metabolism*
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism*

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • p21-Activated Kinases
  • Thrombin
  • rac1 GTP-Binding Protein
  • Calcium