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

Area of Science:

• Cardiovascular Physiology
• Sleep Medicine
• Molecular Biology

Background:

• Sleep apnea (SA) is linked to hypertension, stroke, and cardiac death.
• Intermittent hypoxia (IH), a model for SA, elevates blood pressure and endothelin-1 (ET-1) levels.
• NFAT activity is increased in IH-exposed mice, and NFATc3 ablation prevents IH-induced hypertension.

Purpose of the Study:

• To investigate the hypothesis that IH increases arterial ROS, activating NFATc3 and enhancing vasoconstrictor reactivity to ET-1.
• To elucidate the role of ROS and NFATc3 in IH-induced hypertension.

Main Methods:

• Utilized an intermittent hypoxia with CO2 supplementation (IH) model in rats and mice.
• Measured blood pressure, ET-1 levels, pre-pro ET-1 mRNA, vascular reactivity, ROS production, and NFAT activity.
• Employed genetic ablation of NFATc3 and in vivo administration of the SOD mimetic tempol.

Main Results:

• IH exposure increased ROS in the aorta and mesenteric arteries.
• Tempol administration prevented IH-induced increases in NFAT activity.
• IH caused an NFATc3-dependent increase in vasoconstrictor reactivity to ET-1 and elevated vessel wall [Ca²⁺].

Conclusions:

• IH exposure increases arterial ROS, activating NFATc3, which enhances vasoconstrictor and Ca²⁺ responses to ET-1.
• This pathway highlights a novel mechanism contributing to hypertension in sleep apnea.
• NFAT inhibition presents a potential therapeutic strategy for hypertension in SA patients.