Abstract 18371: Protective Role of Myelocytic Nitric Oxide Synthases in Hypoxic Pulmonary Hypertension in Mice
Background: All three nitric oxide synthase isoforms (nNOS, iNOS, and eNOS) are expressed under pulmonary hypertensive conditions. The role of entire NOSs in pulmonary hypertension (PH) has been examined in pharmacological studies with non-selective NOSs inhibitors. However, obtained results are quite inconsistent possibly due to non-specificity of the inhibitors. We addressed this point in mice in which all the NOS genes are completely disrupted.
Methods and Results: Wild-type (WT), single nNOS-/-, iNOS-/-, eNOS-/-, and triple n/i/eNOSs-/- mice were exposed to hypoxia for 3 weeks (n=6-28). Hypoxic exposure significantly reduced survival rate only in the triple NOSs-/- genotype. Hypoxic exposure increased right ventricular pressure (RVP), right ventricular hypertrophy (RVH), and medial thickening of the pulmonary artery (MT) in all the genotypes. Notably, RVP were markedly exacerbated in the triple NOSs-/- genotype, and, to a lesser extent, in the eNOS-/- genotype, but not in the nNOS-/- or iNOS-/- genotype, as compared with the WT genotype, and RVH and MT were markedly deteriorated only in the triple NOSs-/- genotype compared with the WT genotype. In the triple NOSs-/- genotype exposed to hypoxia, the number of circulating bone marrow (BM)-derived vascular smooth muscle cell (VSMC) progenitor cells was significantly increased, and transplantation of green fluorescent protein-transgenic BM revealed contribution of BM cells to pulmonary artery remodeling. Importantly, transplantation of triple NOSs-/- BM into the WT genotype aggravated PH, and transplantation of WT BM into the triple NOSs-/- genotype ameliorated PH. In the lung of the WT genotype with the triple NOSs-/- BM transplantation as compared with that with the WT BM transplantation, mRNA levels of tumor necrosis factor-alpha and matrix metalloproteinase-7 were significantly increased, and those of Cu,Zn-superoxide dismutase (SOD) and Mn-SOD were significantly decreased, suggesting an involvement of inflammation and oxidative stress.
Conclusions: These results provide the first evidence that genetic disruption of all NOSs, specifically in BM cells, markedly exacerbates hypoxic PH in mice, demonstrating the novel protective role of myelocytic NOSs in the pathogenesis of PH.
Author Disclosures: M. Tsutsui: None. T. Ogoshi : None. T. Kido: None. S. Yamada: None. K. Wang: None. Y. Toyohira: None. H. Shimokawa: Speakers Bureau; Modest; Daiichi-Sankyo, Bayer Yakuhin. N. Yanagihara: None. N. Yanagihara: None. K. Yatera: None. H. Mukae : None.
- © 2016 by American Heart Association, Inc.