1. GATA6 coordinates cross-talk between BMP10 and oxidative stress axis in pulmonary arterial hypertension.
- Author
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Toyama T, Kudryashova TV, Ichihara A, Lenna S, Looney A, Shen Y, Jiang L, Teos L, Avolio T, Lin D, Kaplan U, Marden G, Dambal V, Goncharov D, Delisser H, Lafyatis R, Seta F, Goncharova EA, and Trojanowska M
- Subjects
- Animals, Mice, Cell Proliferation, Cells, Cultured, Familial Primary Pulmonary Hypertension pathology, Myocytes, Smooth Muscle metabolism, Pulmonary Artery pathology, Vascular Remodeling, Bone Morphogenetic Proteins genetics, Bone Morphogenetic Proteins metabolism, GATA6 Transcription Factor genetics, GATA6 Transcription Factor metabolism, Oxidative Stress, Pulmonary Arterial Hypertension genetics, Pulmonary Arterial Hypertension metabolism, Pulmonary Arterial Hypertension pathology
- 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., (© 2023. The Author(s).)
- Published
- 2023
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