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Am J Physiol Lung Cell Mol Physiol 297: L475-L486, 2009. First published July 10, 2009; doi:10.1152/ajplung.00060.2009
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Regulation of soluble guanylyl cyclase-{alpha}1 expression in chronic hypoxia-induced pulmonary hypertension: role of NFATc3 and HuR

Sergio de Frutos, Carlos H. Nitta, Elizabeth Caldwell, Jessica Friedman, and Laura V. González Bosc

Vascular Physiology Group, Department of Cell Biology and Physiology, School of Medicine, University of New Mexico, Albuquerque, New Mexico

Submitted 24 February 2009 ; accepted in final form 9 July 2009

The nitric oxide/soluble guanylyl cyclase (sGC) signal transduction pathway plays an important role in smooth muscle relaxation and phenotypic regulation. However, the transcriptional regulation of sGC gene expression is largely unknown. It has been shown that sGC expression increases in pulmonary arteries from chronic hypoxia-induced pulmonary hypertensive animals. Since the transcription factor NFATc3 is required for the upregulation of the smooth muscle hypertrophic/differentiation marker {alpha}-actin in pulmonary artery smooth muscle cells from chronically hypoxic mice, we hypothesized that NFATc3 is required for the regulation of sGC-{alpha}1 expression during chronic hypoxia. Exposure to chronic hypoxia for 2 days induced a decrease in sGC-{alpha}1 expression in mouse pulmonary arteries. This reduction was independent of NFATc3 but mediated by nuclear accumulation of the mRNA-stabilizing protein human antigen R (HuR). Consistent with our hypothesis, chronic hypoxia (21 days) upregulated pulmonary artery sGC-{alpha}1 expression, bringing it back to the level of the normoxic controls. This response was prevented in NFATc3 knockout and cyclosporin (calcineurin/NFATc inhibitor)-treated mice. Furthermore, we identified effective binding sites for NFATc in the mouse sGC-{alpha}1 promoter. Activation of NFATc3 increased sGC-{alpha}1 promoter activity in human embryonic derived kidney cells, rat aortic-derived smooth muscle cells, and human pulmonary artery smooth muscle cells. Our results suggest that NFATc3 and HuR are important regulators of sGC-{alpha}1 expression in pulmonary vascular smooth muscle cells during chronic hypoxia-induced pulmonary hypertension.

human antigen R; nuclear factor of activated T cells isoform c3


Address for reprint requests and other correspondence: L. V. González Bosc, Dept. of Cell Biology and Physiology, School of Medicine, Univ. of New Mexico, MSC 08 4750, Albuquerque, NM 87131 (e-mail: lgonzalezbosc{at}salud.unm.edu)






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