Reciprocal regulation of rac1 and PAK-1 by HIF-1α: A positive-feedback loop promoting pulmonary vascular remodeling

Isabel Diebold, Andreas Petry, Talija Djordjevic, Rachida S. Belaiba, Jeffrey Fineman, Stephen Black, Christian Schreiber, Sohrab Fratz, John Hess, Thomas Kietzmann, Agnes Görlach

Research output: Contribution to journalArticle

43 Scopus citations

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-1α was associated with pulmonary vascular remodeling. Here we studied whether PAK-1 and HIF-1α 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-1α 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-1α expression involving ROS and NF-κB, 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-1α by thrombin and ROS, thus explaining elevated levels of PAK-1, Rac1, and HIF-1α in remodeled pulmonary vessels.

Original languageEnglish (US)
Pages (from-to)399-412
Number of pages14
JournalAntioxidants and Redox Signaling
Volume13
Issue number4
DOIs
StatePublished - Aug 15 2010

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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    Diebold, I., Petry, A., Djordjevic, T., Belaiba, R. S., Fineman, J., Black, S., Schreiber, C., Fratz, S., Hess, J., Kietzmann, T., & Görlach, A. (2010). Reciprocal regulation of rac1 and PAK-1 by HIF-1α: A positive-feedback loop promoting pulmonary vascular remodeling. Antioxidants and Redox Signaling, 13(4), 399-412. https://doi.org/10.1089/ars.2009.3013