title: NFAT is required for spontaneous pulmonary hypertension in superoxide dismutase 1 knockout mice.
abstract: Elevated reactive oxygen species are implicated in pulmonary hypertension (PH). Superoxide dismutase (SOD) limits superoxide bioavailability, and decreased SOD activity is associated with PH. A decrease in SOD activity is expected to increase superoxide and reduce hydrogen peroxide levels. Such an imbalance of superoxide/hydrogen peroxide has been implicated as a mediator of nuclear factor of activated T cells (NFAT) activation in epidermal cells. We have shown that NFATc3 is required for chronic hypoxia-induced PH. However, it is unknown whether NFATc3 is activated in the pulmonary circulation in a mouse model of decreased SOD1 activity and whether this leads to PH. Therefore, we hypothesized that an elevated pulmonary arterial superoxide/hydrogen peroxide ratio activates NFATc3, leading to PH. We found that SOD1 knockout (KO) mice have elevated pulmonary arterial wall superoxide and decreased hydrogen peroxide levels compared with wild-type (WT) littermates. Right ventricular systolic pressure (RVSP) was elevated in SOD1 KO and was associated with pulmonary arterial remodeling. Vasoreactivity to endothelin-1 was also greater in SOD1 KO vs. WT mice. NFAT activity and NFATc3 nuclear localization were increased in pulmonary arteries from SOD1 KO vs. WT mice. Administration of A-285222 (selective NFAT inhibitor) decreased RVSP, arterial wall thickness, vasoreactivity, and NFAT activity in SOD1 KO mice to WT levels. The SOD mimetic, tempol, also reduced NFAT activity, NFATc3 nuclear localization, and RVSP to WT levels. These findings suggest that an elevated superoxide/hydrogen peroxide ratio activates NFAT in pulmonary arteries, which induces vascular remodeling and increases vascular reactivity leading to PH.
authors.affiliation: Vascular Physiology Group, Department of Cell Biology and Physiology, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Ramiro-Diaz
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Nitta
authors.forename: Levi D
authors.initials: LD
authors.lastname: Maston
authors.forename: Simon
authors.initials: S
authors.lastname: Codianni
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Giermakowska
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Resta
authors.forename: Laura V
authors.initials: LV
authors.lastname: Gonzalez Bosc
mesh_terms: D000818:Animals; D003497:Cyclic N-Oxides / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000209:etiology*; D000860:Hypoxia / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D011651:Pulmonary Artery / Q000503:physiopathology; D011720:Pyrazoles / Q000494:pharmacology; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000172:deficiency*; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism
chemical_list: C494244:A 285222; D003497:Cyclic N-Oxides; D019332:Endothelin-1; D050778:NFATC Transcription Factors; D011720:Pyrazoles; D013113:Spin Labels; C445503:transcription factor NF-AT c3; D013481:Superoxides; D006861:Hydrogen Peroxide; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C001803:tempol
keywords: chronic hypoxia; endothelin-1; hydrogen peroxide; nuclear factor of activated T cells c3; pulmonary arterial remodeling; pulmonary hypertension; superoxide; vasoreactivity