Reshaping the Preterm Heart: Shifting Cardiac Renin-Angiotensin System Towards Cardioprotection in Rats Exposed to Neonatal High-Oxygen Stress

Background: Approximately 10% of infants are born preterm. Preterm birth leads to short and long-term changes in cardiac shape and function. By using a rat model of neonatal high-oxygen (80%O-2) exposure, mimicking the premature hyperoxic transition to the extrauterine environment, we revealed a major role of the renin-angiotensin system peptide Angio II (angiotensin II) and its receptor AT1 (angiotensin receptor type 1) on neonatal O-2-induced cardiomyopathy. Here, we tested whether treatment with either orally active compounds of the peptides Angio-(1-7) or alamandine included in cyclodextrin could prevent postnatal cardiac remodeling and the programming of cardiomyopathy induced by neonatal high-O-2 exposure. Methods: Sprague-Dawley pups were exposed to room air or 80% O-2 from postnatal day 3 (P3) to P10. Neonatal rats were treated orally from P3 to P10 and assessed at P10 and P28. Left ventricular (LV) shapes were characterized by tridimensional computational atlases of ultrasound images in addition to histomorphometry. Results: At P10, high O-2-exposed rats presented a smaller, globular and hypertrophied LV shape versus controls. Treatment with cyclodextrin-Angio-(1-7) significantly improved LV function in the O-2-exposed neonatal rats and slightly changed LV shape. Cyclodextrin-alamandine and cyclodextrin-Angio-(1-7) treatments similarly reduced hypertrophy at P10 as well as LV remodeling and dysfunction at P28. Both treatments upregulated cardiac angiotensin-converting enzyme 2 in O-2-exposed rats at P10 and P28. Conclusions: Our findings demonstrate LV remodeling changes induced by O-2-stress and the potential benefits of treatments targeting the cardioprotective renin-angiotensin system axis, supporting the neonatal period as an important window for interventions aiming at preventing cardiomyopathy in people born preterm.