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Mechanisms of NFAT activation during CH
Author(s) -
Frutos Garcia Sergio,
Alo Dominique,
Bosc Laura Gonzalez
Publication year - 2008
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.22.1_supplement.960.19
Subject(s) - nfat , calcineurin , chemistry , pharmacology , activator (genetics) , endocrinology , medicine , receptor , transplantation
Physiological responses to CH include polycythemia, pulmonary arterial (PA) remodeling and vasoconstriction leading to pulmonary hypertension. We have recently demonstrated that NFATc3 is activated in PA from CH mice and it mediates CH‐induced PA remodeling with increased α‐actin expression. Our aim was to evaluate the mechanisms of CH‐induced NFAT activation in PA. 9xNFAT‐luciferase reporter mice were exposed to normoxia (N, 630 torr) or CH (380 torr) for 2 days. The animals were treated subcutaneously or by osmotic pumps with the calcineurin/NFAT inhibitor cyclosporin A (CsA, 25 mg/Kg/day); the non‐selective endothelin (ET) receptors antagonist PD145065 (0.1 mg/kg/day); the L‐type Ca 2+ channel blocker diltiazem (100 mg/kg/day); the Rho kinase (ROK) inhibitor HA‐1077 (30 mg/kg/day) or vehicle (V). CH‐induced NFAT activation in PA was significantly inhibited by CsA and diltiazem, demonstrating the already established role of intracellular Ca 2+ as an activator of calcineurin/NFAT pathway. ROK activity increases in CH and this pathway has been shown to activate NFAT in immune cells. Consistently, we found that HA‐1077 significantly attenuated CH‐induced NFAT activation. ET‐1 is an important factor in the development of pulmonary hypertension, also it is a potent activator of NFATc3 ex vivo but in the current study PD145065 failed to prevent NFAT activation. In conclusion, Ca 2+ /calcineurin and ROK seem to mediate CH‐induced NFAT activation in PA. Supported by American Lung Association.