TY - JOUR
T1 - Protective role of myelocytic nitric oxide synthases against hypoxic pulmonary hypertension in mice
AU - Ogoshi, Takaaki
AU - Tsutsui, Masato
AU - Kido, Takashi
AU - Sakanashi, Mayuko
AU - Naito, Keisuke
AU - Oda, Keishi
AU - Ishimoto, Hiroshi
AU - Yamada, Sohsuke
AU - Wang, Ke Yong
AU - Toyohira, Yumiko
AU - Izumi, Hiroto
AU - Masuzaki, Hiroaki
AU - Shimokawa, Hiroaki
AU - Yanagihara, Nobuyuki
AU - Yatera, Kazuhiro
AU - Mukae, Hiroshi
N1 - Funding Information:
Supported in part by Grants-in-Aid for Young Scientists 26860620 and Scientific Research 16K09519 from the Japan Society for the Promotion of Science, a University of Occupational and Environmental Health Research Grant for Promotion of Occupational Health, and a Grant for the Promotion of Advanced Medicine from the Okinawa Prefecture, Japan.
Publisher Copyright:
Copyright © 2018 by the American Thoracic Society.
PY - 2018/7/15
Y1 - 2018/7/15
N2 - 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.
AB - 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.
KW - Bone marrow
KW - Pulmonary vascular remodeling
KW - Right ventricular hypertrophy
KW - Vascular smooth muscle progenitor cell
UR - http://www.scopus.com/inward/record.url?scp=85050164591&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85050164591&partnerID=8YFLogxK
U2 - 10.1164/rccm.201709-1783OC
DO - 10.1164/rccm.201709-1783OC
M3 - Article
C2 - 29480750
AN - SCOPUS:85050164591
VL - 198
SP - 232
EP - 244
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
SN - 1073-449X
IS - 2
ER -