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Reactive Oxygen Species‐Mediated Activation of NFAT Leads to Pulmonary Hypertension
Author(s) -
Bosc Laura Gonzalez,
Nitta Carlos,
Friedman Jessica
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1023.1
Subject(s) - nfat , reactive oxygen species , calcineurin , superoxide dismutase , chemistry , medicine , endocrinology , pulmonary hypertension , sod1 , right ventricular hypertrophy , ventricular pressure , oxidative stress , biochemistry , blood pressure , transplantation
Reactive oxygen species (ROS) are known to be elevated in pulmonary hypertension. ROS has been shown to activate the Ca +2 ‐calcineurin‐NFAT pathway. We have shown that NFATc3 is activated in pulmonary arteries (PA) from chronic hypoxia (CH) mice. Also, NFATc3 is required for CH‐induced pulmonary arterial hypertension (PAH). We hypothesized that elevated ROS levels increase NFAT activity leading to PAH in superoxide dismutase 1 −/− mice (SOD1). To test this hypothesis, we backcrossed NFAT‐luciferase reporter mice with SOD1 +/− until NFAT‐luciferase/SOD1 +/+ and −/− were generated. Right ventricular systolic pressure (RVSP) and right ventricle/total heart weight (% RV/T) were measured in four month old mice. Intra PA were isolated to measure luciferase activity which reflects NFAT activation. Lung sections were stained with dihydroethidium to determine ROS levels. Results: NFAT activity is significantly elevated in PA from SOD1 −/− vs. SOD1 +/+ mice (0.9±0.1 vs. 0.5±0.1 AU/μg protein, 7, p<0.02). RVSP is also significantly elevated in SOD1 −/− (31.4±3.6 vs. 22.2±2.2 mmHg, 5, p<0.05) although RV hypertrophy was not observed. ROS levels were significantly elevated in PA from SOD1 −/− . These results suggest that increased ROS levels in the SOD1 −/− mice lead to NFAT‐mediated PAH. Future studies will address this possibility by inhibiting NFAT in the SOD1 −/− to reverse the elevated RVSP. Supported by NIH R01HL088151.