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-alpha-actin and -myosin heavy chain. NFATc3 (nuclear factor of activated T cells isoform c3), which is aCa(2+)-dependent transcription factor, has been recently linked to smooth muscle phenotypic maintenance through the regulation of the expression of alpha-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 alpha-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 alpha-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 alpha-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.
Highlights
Pulmonary vasoconstriction is thought to be caused by elevated vascular tone through increased pulmonary arterial smooth muscle cell (PASMC) intracellular Ca2ϩ ([Ca2ϩ]i) [3,4,5,6,7,8] and increased sensitivity of the contractile apparatus to Ca2ϩ (9 –12)
CH Increases NFAT Activity and NFATc3 Nuclear Accumulation in Pulmonary Arteries—Most of the mediators of NFAT activation are up-regulated during CH, including PASMC [Ca2ϩ]i, angiotensin II (Ang II) (36 –38), and endothelin 1 (ET-1) (4;6 – 8;47;48), there are no reports of hypoxic activation of NFAT either in vivo or in vitro
The present study examined effects of CH on NFAT activity in pulmonary arteries and determined the role of NFAT in the vascular remodeling that underlies CH-induced pulmonary hypertension
Summary
Pulmonary vasoconstriction is thought to be caused by elevated vascular tone through increased pulmonary arterial smooth muscle cell (PASMC) intracellular Ca2ϩ ([Ca2ϩ]i) [3,4,5,6,7,8] and increased sensitivity of the contractile apparatus to Ca2ϩ (9 –12). Regardless of the cause of pulmonary hypertension, the structural change that is thought to underlie the increased vascular resistance is remodeling of small pulmonary arteries. Medial enlargement is caused by hypertrophy and hyperplasia of the pre-existing smooth muscle cells (reviewed in Ref. 1). Smooth muscle is phenotypically dynamic and maintains its differentiated phenotype through the regulated expression of a repertoire of SM-specific genes (reviewed in Ref. 14 –17). NFAT (nuclear factor of activated T cells), a Ca2ϩ-dependent transcription factor that regulates the expression of genes in both immune and non-immune cells [18, 19], has been recently linked to smooth muscle phenotypic maintenance (20 –25). The NFAT family consists of four members (NFATc1, NFATc2, NFATc3, NFATc4) that share the property of Ca2ϩ/ calcineurin-dependent nuclear translocation, and a fifth mem-
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