Submitted on February 7, 2008
Revised on March 13, 2008
Accepted on March 19, 2008
NFATc3 is required for intermittent hypoxia-induced hypertension
Sergio de Frutos1, Laura Duling1, Dominique Alo1, Tammy Berry1, Olan Jackson-Weaver1, Mary K. Walker Ph.D1, Nancy L. Kanagy2, and Laura V Gonzalez Bosc1*
1 University of New Mexico
2 University of New Mexico School of Medicine
* To whom correspondence should be addressed. E-mail: lgonzalezbosc{at}salud.unm.edu.
Sleep apnea is intermittent respiratory arrest during sleeping associated with increased incidence of hypertension and peripheral vascular disease. Exposing rodents to brief periods of intermittent hypercarbic/hypoxia (H-IH) during sleep mimics the cyclical hypoxia/normoxia of sleep apnea. Endothelin-1, an upstream activator of 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/hr to 5% O2/5% CO2 for 7 hr/day) induces systemic hypertension in mice (MAP mmHg: 97 ± 2 vs. 124 ± 2, p<0.05, n=5) and increases NFATc3 transcriptional activity in aorta and mesenteric arteries. Cyclosporin A (CsA), NFAT inhibitor, and the genetic ablation of NFATc3 (KO) prevented NFAT activation. More importantly, H-IH-induced hypertension was attenuated in CsA-treated and prevented in NFATc3 KO mice. Wildtype mice showed a significant elevation in MAP (
23.5±6.1 mmHg) whereas MAP did not increase in the KO mice ( -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.
