Intermittent hypoxia/hypercapnia (IH) activates NFAT (nuclear factor of activated T‐cells) in the cardiovascular system of mice

Abstract

Obstructive sleep apnea (OSA) is defined as intermittent respiratory arrest during sleeping and is associated with increased incidence of hypertension, peripheral vascular disease, stroke and sudden cardiac death. During the apneas, plasma oxygen content is decreased (hypoxia) and plasma carbon dioxide content is increased (hypercapnia). Exposing rodents to brief periods of IH during sleep mimics the cyclical hypoxia/normoxia of OSA. The goal of this study was to determine if IH increases mean arterial pressure (MAP) and endothelin 1 (ET-1) tissue levels in mice in correlation with an increase in NFAT transcriptional activity in the heart and systemic vasculature. MAP and heart rate were measured by telemetry in FVBN male mice exposed to air-air cycles for 7 control days and then up to 24 days of IH cycling during their sleep period (20 brief exposures/hr to 5% O2/5% CO2) for 7 hr/day. IH animals showed a significant (p<0.05) elevation in MAP after day 3 of exposure, which remained elevated until the end of the experiment (MAP mmHg: 97 ± 2 vs. 124 ± 2, n=5). No differences between groups were observed in heart rate. Lung ET-1 mRNA significantly increased after 2 days of IH (3.9 ± 0.3 fold, n=3). 9xNFAT-luciferase male mice (FVBN background) showed a significant elevation in reporter activity in right and left ventricle, mesenteric arteries, and aorta after IH exposure. These results indicate that IH exposure in mice increases MAP, ET-1 and NFAT transcriptional activity. Therefore, NFAT may contribute to the vascular changes associated with IH-induced hypertension. Supported by SDG AHA.