Intermittent hypoxia-induced increases in reactive oxygen species activate NFATc3 increasing endothelin-1 vasoconstrictor reactivity

J. K. Friedman, C. H. Nitta, K. M. Henderson, S. J. Codianni, L. Sanchez, J. M. Ramiro-Diaz, T. A. Howard, W. Giermakowska, N. L. Kanagy, L. V. Gonzalez Bosc

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Sleep apnea (SA), defined as intermittent respiratory arrest during sleep, is associated with increased incidence of hypertension, peripheral vascular disease, stroke, and sudden cardiac death. We have shown that intermittent hypoxia with CO2 supplementation (IH), a model for SA, increases blood pressure and circulating ET-1 levels, upregulates lung pre-pro ET-1 mRNA, increases vasoconstrictor reactivity to ET-1 in rat small mesenteric arteries (MA) and increases vascular reactive oxygen species (ROS). NFAT activity is increased in the aorta (AO) and MA of mice exposed to IH in an ET-1-dependent manner, and the genetic ablation of the isoform NFATc3 prevents IH-induced hypertension. We hypothesized that IH causes an increase in arterial ROS generation, which activates NFATc3 to increase vasoconstrictor reactivity to ET-1. In support of our hypothesis, we found that IH increases ROS in AO and MA. In vivo administration of the SOD mimetic tempol during IH exposure prevents IH-induced increases in NFAT activity in mouse MA and AO. We found that IH causes an NFATc3-dependent increase in vasoconstrictor reactivity to ET-1, accompanied by an increase in vessel wall [Ca2+]. Our results indicate that IH exposure causes an increase in arterial ROS to activate NFATc3, which then increases vasoconstrictor reactivity and Ca2+ response to ET-1. These studies highlight a novel regulatory pathway, and demonstrate the potential clinical relevance of NFAT inhibition to prevent hypertension in SA patients.

Original languageEnglish (US)
Pages (from-to)17-24
Number of pages8
JournalVascular Pharmacology
Volume60
Issue number1
DOIs
StatePublished - Jan 2014

Keywords

  • Arteries
  • Hypertension
  • Intermittent hypoxia
  • Oxidative stress
  • Sleep apnea

ASJC Scopus subject areas

  • Physiology
  • Molecular Medicine
  • Pharmacology

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    Friedman, J. K., Nitta, C. H., Henderson, K. M., Codianni, S. J., Sanchez, L., Ramiro-Diaz, J. M., Howard, T. A., Giermakowska, W., Kanagy, N. L., & Gonzalez Bosc, L. V. (2014). Intermittent hypoxia-induced increases in reactive oxygen species activate NFATc3 increasing endothelin-1 vasoconstrictor reactivity. Vascular Pharmacology, 60(1), 17-24. https://doi.org/10.1016/j.vph.2013.11.001