Cannabidiol Protects the Neonatal Mouse Heart from Hyperoxia-Induced Injury

Neonatal hyperoxia induces oxidative and inflammatory stress that disrupts cardiac maturation and contributes to long-term cardiovascular morbidity in individuals born preterm. Cannabidiol (CBD), a non-psychoactive phytocannabinoid with antioxidant and anti-inflammatory properties, has demonstrated protective effects in neonatal hyperoxic injury in other organs; however, its impact on the developing heart remains unclear. This study investigated whether CBD mitigates hyperoxia-induced cardiac injury in a neonatal mouse model. Newborn mice were exposed to 80% O₂ for 48 h from postnatal day (P)5 to P7 and received vehicle, 10 mg/kg CBD, or 30 mg/kg CBD intraperitoneally, while controls remained in room air. Hearts were collected at P7 or after recovery until P14. Hyperoxia triggered oxidative stress (<i>Nrf2</i>), inflammation (<i>IL1β</i>, <i>TNFα</i>, <i>IL6</i>, <i>CXCL1</i>; <i>p</i> < 0.05), and dysregulated apoptosis/autophagy, leading to reduced cardiomyocyte proliferation (Ki67⁺ -50% at P14; <i>p</i> < 0.01) and adverse remodeling (hypertrophy, fibrosis; <i>p</i> < 0.01). CBD attenuated these responses and normalized autophagy (<i>Atg5</i>, <i>Atg12</i>; <i>p</i> < 0.05). Notably, 10 mg/kg CBD, but not 30 mg/kg, preserved proliferative capacity and reduced wall thickness, suggesting a narrow therapeutic window, while both doses limited collagen deposition and apoptosis (<i>Casp3</i>, <i>AIF</i>; <i>p</i> < 0.05). Several effects were sex-dependent, with males exhibiting more pronounced long-term structural and proliferative impairments and greater responsiveness to low-dose CBD. These findings identify CBD as a potential cardioprotective modulator of neonatal hyperoxia-induced injury and highlight the importance of dose- and sex-specific mechanisms in early cardiac maturation.