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Publications

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Epublish 10 citations

PubMed: 37087509 DOI: 10.1038/s41598-023-33779-8

GATA6 coordinates cross-talk between BMP10 and oxidative stress axis in pulmonary arterial hypertension.

Sci Rep 13(1):6593

Authors: Tetsuo Toyama, Tatiana V Kudryashova, Asako Ichihara, Stefania Lenna, Agnieszka Looney, Yuanjun Shen, Lifeng Jiang, Leyla Teos, Theodore Avolio, Derek Lin, Ulas Kaplan, Grace Marden, Vrinda Dambal, Dmitry Goncharov, Horace Delisser, Robert Lafyatis, Francesca Seta, Elena A Goncharova, Maria Trojanowska

Affiliations

  • Arthritis and Autoimmune Diseases Center, Boston University School of Medicine, 75 E. Newton St. Evans Building, Boston, MA, 02118, USA.
  • Pittsburgh Lung, Blood and Heart Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Division of Pulmonary, Allergy and Critical Care, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Division of Pulmonary, Critical Care, and Sleep Medicine, Davis School of Medicine, University of California, Davis, CA, USA.
  • Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Division of Rheumatology and Clinical Rheumatology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • Pittsburgh Lung, Blood and Heart Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Division of Pulmonary, Allergy and Critical Care, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Division of Pulmonary, Critical Care, and Sleep Medicine, Davis School of Medicine, University of California, Davis, CA, USA.
  • The Genome and Biomedical Science Facility (GBSF), Rm 6523, 451 Health Sciences Drive, Davis, CA, 95616, USA.
  • Arthritis and Autoimmune Diseases Center, Boston University School of Medicine, 75 E. Newton St. Evans Building, Boston, MA, 02118, USA.

Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and often death. Here we report that deficiency of transcription factor GATA6 is a shared pathological feature of PA endothelial (PAEC) and smooth muscle cells (PASMC) in human PAH and experimental PH, which is responsible for maintenance of hyper-proliferative cellular phenotypes, pulmonary vascular remodeling and pulmonary hypertension. We further show that GATA6 acts as a transcription factor and direct positive regulator of anti-oxidant enzymes, and its deficiency in PAH/PH pulmonary vascular cells induces oxidative stress and mitochondrial dysfunction. We demonstrate that GATA6 is regulated by the BMP10/BMP receptors axis and its loss in PAECs and PASMC in PAH supports BMPR deficiency. In addition, we have established that GATA6-deficient PAEC, acting in a paracrine manner, increase proliferation and induce other pathological changes in PASMC, supporting the importance of GATA6 in pulmonary vascular cell communication. Treatment with dimethyl fumarate resolved oxidative stress and BMPR deficiency, reversed hemodynamic changes caused by endothelial Gata6 loss in mice, and inhibited proliferation and induced apoptosis in human PAH PASMC, strongly suggesting that targeting GATA6 deficiency may provide a therapeutic advance for patients with PAH.

MeSH

Transcription Factors, Antioxidants, Oxidative Stress, Stress, Physiological, Cells, Therapeutics, Gata6 Transcription Factor, Pulmonary Arterial Hypertension

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