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NFAT plays a role in chronic hypoxia‐induced pulmonary arterial hypertension
Author(s) -
de Frutos Sergio,
Spangler Rhyan,
Bosc Laura Gonzalez
Publication year - 2006
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.20.4.a404-c
Subject(s) - nfat , hypoxia (environmental) , right ventricular hypertrophy , hypoxic pulmonary vasoconstriction , pulmonary hypertension , chemistry , vascular remodelling in the embryo , medicine , downregulation and upregulation , muscle hypertrophy , calcineurin , endocrinology , pulmonary artery , lung , biochemistry , oxygen , transplantation , organic chemistry , gene
Physiological responses to chronic hypoxia (CH) include polycythemia, pulmonary arterial remodeling and vasoconstriction. CH causes pulmonary arterial hypertension (PAH) leading to right ventricular hypertrophy (RVH). The aim of this study was to evaluate the role of the Ca 2+ ‐dependent transcription factor, NFAT, in CH‐induced PAH. Wild type mice (WT) were exposed to normoxia (N, 630 torr) or CH (380 torr) for 1 wk. The animals were treated with the calcineurin/NFAT inhibitor, cyclosporin A (CsA, 25 mg/Kg/day s.c.) or vehicle (V). CH induced RVH only in V‐treated mice (% RV weight/heart weight: NV=20.4× 0.9; NCsA=20.3× 1.1; CHV=25.3× 0.5*; CHCsA=22.7× 0.2; n=4, *p<0.01). However, CsA did not prevent CH‐induced polycythemia. PAH‐induced vascular remodeling is accompanied by increase expression of arterial smooth muscle (SM) contractile proteins such as α‐actin. NFATc3 has been shown to regulate α‐actin promoter activity in cultured SM. In this study, CsA prevented CH‐induced upregulation of α‐actin protein in isolated pulmonary arteries (PA) and whole lung (PA: NV=1.23× 0.07; NCsA=1.06× 0.05; CHV=1.61× 0.07*; CHCsA=1.09× 0.04; n=4, *p<0.01). Confocal immunofluorescence in CHV small PA showed increased VSM nuclear NFATc3 localization compared to NV and CHCsA, supporting a role for NFATc3 in the CH responses. In addition, NFATc3 knockout mice (KO) and WT were exposed to N or CH for 3 wks. CH neither induced RVH nor increased PA α‐actin levels in the KO (PA: NKO=0.74× 0.06; CHKO=0.79× 0.09; n=4). These results strongly suggest NFAT plays a role in CH‐induced arterial remodeling, PAH and RVH. Supported by the Dedicated Health Research Funds of the UNM SOM.