A non-selective endothelin receptor antagonist bosentan modulates kinetics of bone marrow-derived cells in ameliorating pulmonary hypertension in mice

The aim of this study was to investigate whether a dual endothelin receptor antagonist bosentan modulates the kinetics of bone marrow-derived stem cells in inhibiting the development of pulmonary hypertension. Bone marrow chimeric mice, transplanted with enhanced green fluorescent protein (eGFP)-positive bone marrow mononuclear cells, were exposed to hypobaric hypoxia or kept in the ambient air, and were daily treated with bosentan sodium salt or saline for 21 days. After the treatment period, right ventricular pressure was measured and pulmonary vascular morphometry was conducted. Incorporation of bone marrow-derived cells was analyzed by immunohistochemistry. Gene expression and protein level in the lung tissue were evaluated by quantitative real-time PCR and western blotting, respectively. The results showed that, in hypoxic mice, right ventricular pressure and the percentage of muscularized vessel were increased and pulmonary vascular density was decreased, each of which was reversed by bosentan. Bone marrow-derived endothelial cells and macrophages in lungs were increased by hypoxia. Bosentan promoted bone marrow-derived endothelial cell incorporation but inhibited macrophage infiltration into lungs. Quantitative real-time PCR analysis revealed that interleukin 6, stromal cell-derived factor-1, and monocyte chemoattractant protein-1 were upregulated by hypoxia, in which interleukin 6 and monocyte chemoattractant protein-1 were downregulated and stromal cell-derived factor-1 was upregulated by bosentan. Protein level of endothelial nitric oxide synthase (eNOS) in the whole lung was significantly upregulated by hypoxia, which was further upregulated by bosentan. Bosentan modulated kinetics of bone marrow-derived ECs and macrophages and related gene expression in lungs in ameliorating pulmonary hypertension in mice. Altered kinetics of bone marrow-derived stem cells may be a novel mechanism of the endothelin receptor blockade in vivo and confer a new understanding of the therapeutic basis for pulmonary hypertension.

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Topics

Endothelin and Endothelium & Epithelium and Epithelial Transport
Pulmonary Hypertension

Authors

Taichi Kato, Yoshihide Mitani, Masahiro Masuya, Junko Maruyama, Hirofumi Sawada, Hiroyuki Ohashi, Yukiko Ikeyama, Shoichiro Otsuki, Noriko Yodoya, Tsutomu Shinohara, Eri Miyata, Erquan Zhang, Naoyuki Katayama, Hideto Shimpo, Kazuo Maruyama, Yoshihiro Komada, Masahiro Hirayama

Published in:

Pulmonary Circulation Vol 10 : No 2 cover image

April 2020

Pulmonary Circulation Vol 10 : No 2

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