title: NFATc3 is required for intermittent hypoxia-induced hypertension.
abstract: Sleep apnea, defined as intermittent respiratory arrest during sleep, is associated with increased incidence of hypertension and peripheral vascular disease. Exposure of rodents to brief periods of intermittent hypercarbia/hypoxia (H-IH) during sleep mimics the cyclical hypoxia-normoxia of sleep apnea. Endothelin-1, an upstream activator of nuclear factor of activated T cells (NFAT), is increased during H-IH. Therefore, we hypothesized that NFATc3 is activated by H-IH and is required for H-IH-induced hypertension. Consistent with this hypothesis, we found that H-IH (20 brief exposures per hour to 5% O(2)-5% CO(2) for 7 h/day) induces systemic hypertension in mice [mean arterial pressure (MAP) = 97 +/- 2 vs. 124 +/- 2 mmHg, P < 0.05, n = 5] and increases NFATc3 transcriptional activity in aorta and mesenteric arteries. Cyclosporin A, an NFAT inhibitor, and genetic ablation of NFATc3 [NFATc3 knockout (KO)] prevented NFAT activation. More importantly, H-IH-induced hypertension was attenuated in cyclosporin A-treated mice and prevented in NFATc3 KO mice. MAP was significantly elevated in wild-type mice (Delta = 23.5 +/- 6.1 mmHg), but not in KO mice (Delta = -3.9 +/- 5.7). These results indicate that H-IH-induced increases in MAP require NFATc3 and that NFATc3 may contribute to the vascular changes associated with H-IH-induced hypertension.
authors: Department of Cell Biology and Physiology, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA.
authors: Sergio
authors: S
authors: de Frutos
authors: Laura
authors: L
authors: Duling
authors: Dominique
authors: D
authors: Alò
authors: Tammy
authors: T
authors: Berry
authors: Olan
authors: O
authors: Jackson-Weaver
authors: Mary
authors: M
authors: Walker
authors: Nancy
authors: N
authors: Kanagy
authors: Laura
authors: L
authors: González Bosc
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D006973:Hypertension / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D000860:Hypoxia / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012891:Sleep Apnea Syndromes / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D065095:Calcineurin Inhibitors; D019332:Endothelin-1; D050778:NFATC Transcription Factors; C494009:Nfatc3 protein, mouse; D012333:RNA, Messenger; D016572:Cyclosporine; D019703:Calcineurin