title: NFATc3 contributes to intermittent hypoxia-induced arterial remodeling in mice.
abstract: 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.
authors.affiliation: Vascular Physiology Group, Department of Cell Biology and Physiology, School of Medicine, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Sergio
authors.initials: S
authors.lastname: de Frutos
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Caldwell
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Nitta
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Kanagy
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Mary K
authors.initials: MK
authors.lastname: Walker
authors.forename: Laura V
authors.initials: LV
authors.lastname: Gonzalez Bosc
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000199:Actins / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000077300:Bosentan; D004149:Dioxoles / Q000494:pharmacology; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D017930:Genes, Reporter; D006439:Hemodynamics; D018496:Hyperoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D044022:Receptor, Endothelin A / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000199:Actins; D004149:Dioxoles; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D050778:NFATC Transcription Factors; C494009:Nfatc3 protein, mouse; C093322:PD 155080; D047428:Protein Kinase Inhibitors; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil; D000077300:Bosentan