NFATc3 is required for intermittent hypoxia-induced hypertension.
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.
de Frutos
Sergio
S
Department of Cell Biology and Physiology, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA.
Duling
Laura
L
Alò
Dominique
D
Berry
Tammy
T
Jackson-Weaver
Olan
O
Walker
Mary
M
Kanagy
Nancy
N
González Bosc
Laura
L
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
D065095:Calcineurin Inhibitors; D019332:Endothelin-1; D050778:NFATC Transcription Factors; C494009:Nfatc3 protein, mouse; D012333:RNA, Messenger; D016572:Cyclosporine; D019703:Calcineurin