NFATc3 mediates chronic hypoxia-induced pulmonary arterial remodeling with α-actin up-regulation

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Abstract

Physiological responses to chronic hypoxia include polycythemia, pulmonary arterial remodeling, and vasoconstriction. Chronic hypoxia causes pulmonary arterial hypertension leading to right ventricular hypertrophy and heart failure. During pulmonary hypertension, pulmonary arteries exhibit increased expression of smooth muscle-α-actin and -myosin heavy chain. NFATc3 (nuclear factor of activated T cells isoform c3), which is a Ca 2+-dependent transcription factor, has been recently linked to smooth muscle phenotypic maintenance through the regulation of the expression of α-actin. The aim of this study was to determine if: (a) NFATc3 is expressed in murine pulmonary arteries, (b) hypoxia induces NFAT activation, (c) NFATc3 mediates the up-regulation of α-actin during chronic hypoxia, and (d) NFATc3 is involved in chronic hypoxia-induced pulmonary vascular remodeling. NFATc3 transcript and protein were found in pulmonary arteries. NFAT-luciferase reporter mice were exposed to normoxia (630 torr) or hypoxia (380 torr) for 2, 7, or 21 days. Exposure to hypoxia elicited a significant increase in luciferase activity and pulmonary arterial smooth muscle nuclear NFATc3 localization, demonstrating NFAT activation. Hypoxia induced up-regulation of α-actin and was prevented by the calcineurin/NFAT inhibitor, cyclosporin A (25 mg/kg/day s.c.). In addition, NFATc3 knock-out mice did not showed increased α-actin levels and arterial wall thickness after hypoxia. These results strongly suggest that NFATc3 plays a role in the chronic hypoxia-induced vascular changes that underlie pulmonary hypertension. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

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De Frutos, S., Spangler, R., Alò, D., & González Bosc, L. V. (2007). NFATc3 mediates chronic hypoxia-induced pulmonary arterial remodeling with α-actin up-regulation. Journal of Biological Chemistry, 282(20), 15081–15089. https://doi.org/10.1074/jbc.M702679200

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