Luteolin increases baseline apneas and downregulates brainstem HIF in normoxia and chronic intermittent hypoxia

Hypoxia-inducible factor (HIF) is a key regulator of cellular adaptation to reduced oxygen availability. Chronic intermittent hypoxia (CIH), characterized by recurrent cycles of hypoxia and reoxygenation, promotes oxidative stress and activates hypoxia-sensitive signaling pathways involved in ventilatory control. Luteolin-7-O-glucoside (luteolin), a flavonoid with antioxidant and anti-inflammatory properties, has been proposed as a potential modulator of HIF activity. This study evaluated the effects of a 7-day luteolin treatment on the ventilatory pattern and brainstem HIF expression in mice exposed to CIH, a model that mimics a hallmark feature of obstructive sleep apnea. Ventilation was assessed by whole-body plethysmography under baseline normoxic conditions and during an acute hypoxic challenge. Functional assessments revealed that luteolin administration significantly altered the baseline respiratory pattern, increasing the occurrence of apneas during baseline normoxic breathing in both the normoxic and CIH groups. Under baseline conditions, luteolin-treated CIH animals also exhibited a reduced respiratory frequency and an increased tidal volume, without significant changes in minute ventilation. Despite these alterations in baseline breathing, Luteolin treatment did not alter the acute hypoxic ventilatory response (HVR) in either experimental group. To investigate the molecular mechanisms underlying these ventilatory effects, brainstem analysis was performed. Luteolin treatment (10 μg/kg) reduced Hif1a and Epas1 mRNA expression in the brainstem and decreased the number of neurons exhibiting HIF-1α nuclear immunofluorescence within the nucleus of the solitary tract (NTS). Additionally, luteolin reduced Nox4 expression in the brainstem while elevating nitrite levels, suggesting a direct modulation of redox-related pathways. Together, these findings indicate that luteolin alters the baseline respiratory pattern by increasing apnea occurrence in both normoxia and CIH groups under baseline normoxic conditions, an effect potentially linked to the downregulation of brainstem HIF expression and the modulation of local redox state, while the acute ventilatory response to hypoxia remains preserved.