Protective role of myelocytic nitric oxide synthases against hypoxic pulmonary hypertension in mice

Takaaki Ogoshi, Masato Tsutsui, Takashi Kido, Mayuko Sakanashi, Keisuke Naito, Keishi Oda, Hiroshi Ishimoto, Sohsuke Yamada, Ke Yong Wang, Yumiko Toyohira, Hiroto Izumi, Hiroaki Masuzaki, Hiroaki Shimokawa, Nobuyuki Yanagihara, Kazuhiro Yatera, Hiroshi Mukae

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

Rationale: Nitric oxide (NO), synthesized by NOSs (NO synthases), plays a role in the development of pulmonary hypertension (PH). However, the role of NO/NOSs in bone marrow (BM) cells in PH remains elusive. Objectives: To determine the role of NOSs in BM cells in PH. Methods: Experiments were performed on 36 patients with idiopathic pulmonary fibrosis and on wild-type (WT), nNOS (neuronal NOS)2/2, iNOS (inducible NOS)2/2, eNOS (endothelial NOS)2/2, and n/i/eNOSs2/2 mice. Measurements and Main Results: In the patients, there was a significant correlation between higher pulmonary artery systolic pressure and lower nitrite plus nitrate levels in the BAL fluid. In the mice, hypoxia-induced PH deteriorated significantly in the n/i/eNOSs2/2 genotype and, to a lesser extent, in the eNOS2/2 genotype as compared with the WT genotype. In the n/i/eNOSs2/2 genotype exposed to hypoxia, the number of circulating BM-derived vascular smooth muscle progenitor cells was significantly larger, and transplantation of green fluorescent protein–transgenic BM cells revealed the contribution of BM cells to pulmonary vascular remodeling. Importantly, n/i/eNOSs2/2-BM transplantation significantly aggravated hypoxia-induced PH in the WT genotype, and WT-BM transplantation significantly ameliorated hypoxia-induced PH in the n/i/eNOSs2/2 genotype. A total of 69 and 49 mRNAs related to immunity and inflammation, respectively, were significantly upregulated in the lungs of WT genotype mice transplanted with n/i/eNOSs2/2-BM compared with those with WT-BM, suggesting the involvement of immune and inflammatory mechanisms in the exacerbation of hypoxia-induced PH caused by n/i/eNOSs2/2-BM transplantation. Conclusions: These results demonstrate that myelocytic n/i/eNOSs play an important protective role in the pathogenesis of PH.

Original languageEnglish
Pages (from-to)232-244
Number of pages13
JournalAmerican journal of respiratory and critical care medicine
Volume198
Issue number2
DOIs
Publication statusPublished - 2018 Jul 15

Keywords

  • Bone marrow
  • Pulmonary vascular remodeling
  • Right ventricular hypertrophy
  • Vascular smooth muscle progenitor cell

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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