Short-term intermittent hypoxia induces biphasic apoptotic responses in the murine heart

Abstract

Intermittent hypoxia (IH), the defining physiological feature of obstructive sleep apnea, has been strongly linked to cardiovascular morbidity, yet the early myocardial effects of short-term IH remain poorly characterized. In this study, we investigated whether brief IH exposure elicits adaptive anti-apoptotic signaling or early injurious activation of intrinsic apoptotic pathways in the murine heart. Adult male C57BL/6J mice were randomized into four groups (n = 8 per group): room air for 1 day, IH for 1 day, room air for 7 days, and IH for 7 days. IH consisted of alternating 30 s cycles of normoxia (21% O-2) and hypoxia (6% O-2) for 8 h/day for either one day or seven consecutive days. Cardiac tissues from the right ventricle, left ventricle, and interventricular septum were analyzed using histological assessment, apoptotic index quantification, and Western blot analysis of intrinsic apoptotic and hypoxia-related signaling pathways. One day of IH resulted in reduced apoptotic activity and increased expression of the anti-apoptotic protein Bcl-2, consistent with an early adaptive, preconditioning-like response. In contrast, seven days of IH markedly increased apoptosis, and was associated with elevated BAX, cleaved PARP, p53, and HIF-1 alpha expression, indicating activation of intrinsic mitochondrial apoptotic pathways. A more pronounced effect was observed in the right ventricle. Fibrotic remodeling was minimal across all groups, suggesting that apoptosis precedes structural myocardial remodeling. These findings reveal a time-dependent transition from early anti-apoptotic adaptation to intrinsic apoptotic activation during short-term IH exposure and provide insight into the early myocardial consequences of intermittent hypoxia.