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 Matthew Black, Christian Schreiber, Sohrab Fratz, John Hess, Thomas Kietzmann, Agnes Görlach

Research output: Contribution to journalArticle

40 Citations (Scopus)

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

Fingerprint

p21-Activated Kinases
Feedback
Lung
Reactive Oxygen Species
Thrombin
Pulmonary Artery
Smooth Muscle Myocytes
Muscle
Vascular Remodeling
Plasminogen Activator Inhibitor 1
Cell proliferation
Transcription
Pulmonary Hypertension
Thrombosis
Transcription Factors
Genes
Chemical activation
Cells
Cell Proliferation
Tissue

ASJC Scopus subject areas

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

Cite this

Diebold, I., Petry, A., Djordjevic, T., Belaiba, R. S., Fineman, J., Black, S. M., ... 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

Reciprocal regulation of rac1 and PAK-1 by HIF-1α : A positive-feedback loop promoting pulmonary vascular remodeling. / Diebold, Isabel; Petry, Andreas; Djordjevic, Talija; Belaiba, Rachida S.; Fineman, Jeffrey; Black, Stephen Matthew; Schreiber, Christian; Fratz, Sohrab; Hess, John; Kietzmann, Thomas; Görlach, Agnes.

In: Antioxidants and Redox Signaling, Vol. 13, No. 4, 15.08.2010, p. 399-412.

Research output: Contribution to journalArticle

Diebold, I, Petry, A, Djordjevic, T, Belaiba, RS, Fineman, J, Black, SM, 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, vol. 13, no. 4, pp. 399-412. https://doi.org/10.1089/ars.2009.3013
Diebold, Isabel ; Petry, Andreas ; Djordjevic, Talija ; Belaiba, Rachida S. ; Fineman, Jeffrey ; Black, Stephen Matthew ; Schreiber, Christian ; Fratz, Sohrab ; Hess, John ; Kietzmann, Thomas ; Görlach, Agnes. / Reciprocal regulation of rac1 and PAK-1 by HIF-1α : A positive-feedback loop promoting pulmonary vascular remodeling. In: Antioxidants and Redox Signaling. 2010 ; Vol. 13, No. 4. pp. 399-412.
@article{6e84bbb3c1184336905344c8451be9d9,
title = "Reciprocal regulation of rac1 and PAK-1 by HIF-1α: A positive-feedback loop promoting pulmonary vascular remodeling",
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.",
author = "Isabel Diebold and Andreas Petry and Talija Djordjevic and Belaiba, {Rachida S.} and Jeffrey Fineman and Black, {Stephen Matthew} and Christian Schreiber and Sohrab Fratz and John Hess and Thomas Kietzmann and Agnes G{\"o}rlach",
year = "2010",
month = "8",
day = "15",
doi = "10.1089/ars.2009.3013",
language = "English (US)",
volume = "13",
pages = "399--412",
journal = "Antioxidants and Redox Signaling",
issn = "1523-0864",
publisher = "Mary Ann Liebert Inc.",
number = "4",

}

TY - JOUR

T1 - Reciprocal regulation of rac1 and PAK-1 by HIF-1α

T2 - A positive-feedback loop promoting pulmonary vascular remodeling

AU - Diebold, Isabel

AU - Petry, Andreas

AU - Djordjevic, Talija

AU - Belaiba, Rachida S.

AU - Fineman, Jeffrey

AU - Black, Stephen Matthew

AU - Schreiber, Christian

AU - Fratz, Sohrab

AU - Hess, John

AU - Kietzmann, Thomas

AU - Görlach, Agnes

PY - 2010/8/15

Y1 - 2010/8/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77953505608&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953505608&partnerID=8YFLogxK

U2 - 10.1089/ars.2009.3013

DO - 10.1089/ars.2009.3013

M3 - Article

C2 - 20001745

AN - SCOPUS:77953505608

VL - 13

SP - 399

EP - 412

JO - Antioxidants and Redox Signaling

JF - Antioxidants and Redox Signaling

SN - 1523-0864

IS - 4

ER -