In Vitro Modelling of Obstructive Sleep Apnea by Intermittent Hypoxia of Human Embryonic Stem Cell-Derived...

Obstructive sleep apnea (OSA) syndrome is characterized by repetitive nocturnal airway obstruction and is associated with intermittent hypoxia (IH). The leading cause of death among OSA patients is cardiovascular morbidity, which is greatly enhanced by IH. Despite the existence of standard treatment, cardiovascular morbidity remains unaddressed. Given the central role of IH in OSA-related cardiac damage, the present study aimed to elucidate the mechanisms underlying IH-induced cardiac injury in order to better understand and potentially improve upon current therapeutic approaches. Using human embryonic stem cell-derived cardiomyocytes (hESC-CMs) as a novel in vitro model, IH was successfully induced, and its effects on key signaling pathways were investigated. Following IH exposure, significant activation of ERK1/2, ERK5, and Erbin was demonstrated. Notably, the concurrent increase in both ERK1/2 activation and Erbin expression following IH suggests a more complex regulatory relationship between these molecules than previously appreciated. Furthermore, pathway-specific inhibition of ERK1/2 and ERK5 attenuated the IH-induced decline in beating rate, with significant restoration, following normoxic recovery. This study provides an innovative approach for in vitro investigation of OSA-associated cardiovascular morbidity and supports the search for novel pharmacological agents and molecular targets to improve the diagnosis and treatment of affected patients.