NFATc3 is required for chronic hypoxia-induced pulmonary hypertension in adult and neonatal mice

Abstract

LV. NFATc3 is required for chronic hypoxia-induced pulmonary hypertension in adult and neonatal mice. Am J Physiol Lung Cell Mol Physiol 301: L872-L880, 2011. First published September 9, 2011 doi:10.1152/ajplung.00405.2010.-Pulmonary hypertension occurs with prolonged exposure to chronic hypoxia in both adults and neonates. The Ca 2ϩ -dependent transcription factor, nuclear factor of activated T cells isoform c3 (NFATc3), has been implicated in chronic hypoxia-induced pulmonary arterial remodeling in adult mice. Therefore, we hypothesized that NFATc3 is required for chronic hypoxiainduced pulmonary hypertension in adult and neonatal mice. The aim of this study was to determine whether 1) NFATc3 mediates chronic hypoxia-induced increases in right ventricular systolic pressure in adult mice; 2) NFATc3 is activated in neonatal mice exposed to chronic hypoxia; and 3) NFATc3 is involved in chronic hypoxiainduced right ventricular hypertrophy and pulmonary vascular remodeling in neonatal mice. Adult mice were exposed to hypobaric hypoxia for 2, 7, and 21 days. Neonatal mouse pups were exposed for 7 days to hypobaric chronic hypoxia within 2 days after delivery. Hypoxiainduced increases in right ventricular systolic pressure were absent in NFATc3 knockout adult mice. In neonatal mice, chronic hypoxia caused NFAT activation in whole lung and nuclear accumulation of NFATc3 in both pulmonary vascular smooth muscle and endothelial cells. In addition, heterozygous NFATc3 neonates showed less right ventricular hypertrophy and pulmonary artery wall thickness in response to chronic hypoxia than did wild-type neonates. Our results suggest that NFATc3 mediates pulmonary hypertension and vascular remodeling in both adult and neonatal mice. arterial remodeling; right ventricular hypertrophy; nuclear factor of activated T cells reporter activity; pulmonary arterial smooth muscle; pulmonary arterial endothelial cells SECONDARY PULMONARY HYPERTENSION (PH) is caused by a variety of obstructive pulmonary diseases and residence at high altitude, two conditions associated with chronic hypoxia (CH) (20). Pulmonary vascular resistance rises in these settings due to pulmonary vasoconstriction, arterial remodeling, and polycythemia, which results in increased right ventricular systolic pressure (RVSP), right ventricular (RV) hypertrophy, and often heart failure (28). However, there is currently limited availability of novel therapies (34).Persistent PH of the newborn (PPHN) is a cause of significant morbidity and mortality in both term and preterm neonates. The incidence is reported to be 1-2 per 1,000 live births, with a mortality rate from 10 to 20% (22). PPHN is a disorder of vascular transition from fetal to neonatal circulation, which manifests as hypoxemic respiratory failure (22). Mechanisms that interplay in the pathogenesis of PPHN include endothelial dysfunction, inflammation, mechanical strain, and hypoxia (22).PH can be very effectively developed in rodents by exposing them to simulated altitude in a hypobaric chamber; therefo...

Calcineurin/NFAT Signaling Modulates Pulmonary Artery Smooth Muscle Cell Proliferation, Migration and Apoptosis in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats

“…Generally, our results showed that NFATc3 specifically acted on MCT-PASMCs, while silencing of NFATc2 and NFATc4 affected not only MCT-PASMCs but also CON-PASMCs. In addition, NFATc3 has been reported to regulate PASMC proliferation, migration and apoptosis in chronic hypoxia-induced PAH [35,52]. The above information suggests that NFATc3 might be an ideal therapeutic target for PAH due to its effectiveness and selectivity in PAH.…”

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

“…In adult mice, NFATc3 activation contributes to pulmonary arterial wall thickness; conversely, NFATc3 deficient adult mice displayed normal right ventricular systemic pressure after exposure to hypoxia. 29 Interestingly, nucleus accumulation of NFATc3 was observed in both endothelial cells (ECs) and PASMC in the lung of neonatal mice in response to chronic hypoxia. Compared to wild-type neonatal mice, heterozygous NFATc3 neonates showed less severity of PAH under hypoxic condition.…”

MicroRNA-124 Suppresses the Transactivation of Nuclear Factor of Activated T Cells by Targeting Multiple Genes and Inhibits the Proliferation of Pulmonary Artery Smooth Muscle Cells

“…NFATc2 has been shown to be up-regulated and activated in PAH patients (10). Also, in a mouse model of PAH, chronic hypoxia induces the expression and activation of NFATc3, which may contribute to pulmonary hypertension and vascular remodeling (11,12). Intriguingly, NFAT is also activated in hypoxia-treated human PASMC (HPASMC) or the HPASMC isolated from PAH patients, which is associated with increased cell proliferation and resistance to apoptosis (13).…”

“…NFATs are essential for the development of PAH in both human patients and chronic hypoxia-induced PAH animal models (11,12). It has been reported that NFATs are activated by hypoxia treatment in PASMC (10,13).…”