NFATc3 contributes to intermittent hypoxia-induced arterial remodeling in mice

作者：de Frutos Sergio; Caldwell Elizabeth; Nitta Carlos H; Kanagy Nancy L; Wang Jian; Wang Wei; Walker Mary K; Gonzalez Bosc Laura V

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2010, 299(2): H356-H363.

DOI：10.1152/ajpheart.00341.2010

• arteries
• hypertension
• endothelin 1
• Rho kinase

de Frutos S, Caldwell E, Nitta CH, Kanagy NL, Wang J, Wang W, Walker MK, Gonzalez Bosc LV. NFATc3 contributes to intermittent hypoxia-induced arterial remodeling in mice. Am J Physiol Heart Circ Physiol 299: H356-H363, 2010. First published May 21, 2010; doi:10.1152/ajpheart.00341.2010.-Sleep apnea (SA) is defined as intermittent respiratory arrest during sleep and affects up to 20% of the adult population. SA is also associated with an increased incidence of hypertension and peripheral vascular disease. Exposing rodents to intermittent hypoxia during sleep mimics the cyclical hypoxia/normoxia of SA. We have previously shown that in mice and rats intermittent hypoxia induces ET-1 upregulation and systemic hypertension. Furthermore, intermittent hypoxia (IH) in mice increases nuclear factor of activated T cells isoform 3 (NFATc3) transcriptional activity in aorta and mesenteric arteries, whereas the calcineurin/NFAT inhibitor cyclosporin A prevents IH-induced hypertension. More importantly, NFATc3 knockout (KO) mice do not develop IH-induced hypertension. The goals of this study were to determine the role of NFATc3 in IH-induced arterial remodeling and whether IH-induced NFATc3 activation is mediated by ET-1. Oral administration of both a dual (bosentan) and a selective endothelin receptor type A antagonist (PD155080) during 2 days of IH exposure attenuated NFAT activation in aorta and mesenteric arteries. Rho kinase inhibition with fasudil also prevented IH-induced NFAT activation. Mesenteric artery cross-sectional wall thickness was increased by IH in wild-type (WT) and vehicle-treated mice but not in bosentan-treated and NFATc3 KO mice. The arterial remodeling in mesenteric arteries after IH was characterized by increased expression of the hypertrophic NFATc3 target smooth muscle-alpha-actin in WT but not in KO mice. These results indicate that ET-1 is an upstream activator of NFATc3 during intermittent hypoxia, contributing to the resultant hypertension and increased wall thickness.

• 出版日期2010-8