NFATc3 contributes to intermittent hypoxia-induced arterial remodeling in mice

Sergio De Frutos, Elizabeth Caldwell, Carlos H. Nitta, Nancy L. Kanagy, Jian Wang, Wei Wang, Mary K. Walker, Laura V. Gonzalez Bosc

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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-α-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.

Original languageEnglish (US)
Pages (from-to)H356-H363
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume299
Issue number2
DOIs
StatePublished - Aug 2010
Externally publishedYes

Keywords

  • Arteries
  • Endothelin 1
  • Hypertension
  • Rho kinase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Fingerprint

Dive into the research topics of 'NFATc3 contributes to intermittent hypoxia-induced arterial remodeling in mice'. Together they form a unique fingerprint.

Cite this