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- Title
Protective Role of Myelocytic Nitric Oxide Synthases against Hypoxic Pulmonary Hypertension in Mice.
- Authors
Ogoshi, Takaaki; Tsutsui, Masato; Kido, Takashi; Sakanashi, Mayuko; Naito, Keisuke; Oda, Keishi; Ishimoto, Hiroshi; Yamada, Sohsuke; Wang, Ke-Yong; Toyohira, Yumiko; Izumi, Hiroto; Masuzaki, Hiroaki; Shimokawa, Hiroaki; Yanagihara, Nobuyuki; Yatera, Kazuhiro; Mukae, Hiroshi
- Abstract
<bold>Rationale: </bold>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.<bold>Objectives: </bold>To determine the role of NOSs in BM cells in PH.<bold>Methods: </bold>Experiments were performed on 36 patients with idiopathic pulmonary fibrosis and on wild-type (WT), nNOS (neuronal NOS)-/-, iNOS (inducible NOS)-/-, eNOS (endothelial NOS)-/-, and n/i/eNOSs-/- mice.<bold>Measurements and Main Results: </bold>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/eNOSs-/- genotype and, to a lesser extent, in the eNOS-/- genotype as compared with the WT genotype. In the n/i/eNOSs-/- 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/eNOSs-/--BM transplantation significantly aggravated hypoxia-induced PH in the WT genotype, and WT-BM transplantation significantly ameliorated hypoxia-induced PH in the n/i/eNOSs-/- 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/eNOSs-/--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/eNOSs-/--BM transplantation.<bold>Conclusions: </bold>These results demonstrate that myelocytic n/i/eNOSs play an important protective role in the pathogenesis of PH.
- Publication
American Journal of Respiratory & Critical Care Medicine, 2018, Vol 198, Issue 2, p232
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.201709-1783OC