Protective Role of Myelocytic Nitric Oxide Synthases against Hypoxic Pulmonary Hypertension in Mice.

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)-/-, iNOS (inducible NOS)-/-, eNOS (endothelial NOS)-/-, and n/i/eNOSs-/- 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/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.

CONCLUSIONS:

These results demonstrate that myelocytic n/i/eNOSs play an important protective role in the pathogenesis of PH.

• Authors: 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
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 198 Issue 2 Pg. 232-244 (07 15 2018) ISSN: 1535-4970 [Electronic] United States
• PMID: 29480750 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protective Agents
• Nitric Oxide Synthase

Topics

• Animals
• Bone Marrow Cells (drug effects)
• Granulocyte Precursor Cells (drug effects)
• Humans
• Hypertension, Pulmonary (drug therapy, physiopathology)
• Hypoxia (drug therapy, physiopathology)
• Male
• Mice
• Models, Animal
• Nitric Oxide Synthase (therapeutic use)
• Protective Agents (therapeutic use)