Activation of the Cardiac Renin–Angiotensin System in High Oxygen-Exposed Newborn Rats

Abstract

Newborn rats exposed to high oxygen (O₂), mimicking preterm birth-related neonatal stress, develop later in life cardiac hypertrophy, dysfunction, fibrosis, and activation of the renin–angiotensin system. Cardiac renin–angiotensin system activation in O₂-exposed adult rats is characterized by an imbalance in angiotensin (Ang) receptors type 1/2 (AT1/2), with prevailing AT1 expression. To study the role of renin–angiotensin system in the developmental programming of cardiac dysfunction, we assessed Ang receptor expression during neonatal high O₂ exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague–Dawley newborn rats were kept with their mother in 80% O₂ or room air (control) from days 3 to 10 (P3–P10) of life. Losartan or water was administered by gavage from P8 to P10 (n=9/group). Rats were studied at P3 (before O₂ exposure), P5, P10 (end of O₂), and P28. Losartan treatment had no impact on growth or kidney development. AT1 and Ang type 2 receptors were upregulated in the left ventricle by high O₂ exposure (P5 and P10), which was prevented by Losartan treatment at P10. Losartan prevented the cardiac AT1/2 imbalance at P28. Losartan decreased cardiac hypertrophy and fibrosis and improved left ventricle fraction of shortening in P28 O₂-exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-β/SMAD3 pathway, and upregulation of cardiac angiotensin-converting enzyme 2. In conclusion, short-term Ang II blockade during neonatal high O₂ prevents the development of cardiac alterations later in life in rats. These findings highlight the key role of neonatal renin–angiotensin system activation in the developmental programming of cardiac dysfunction induced by deleterious neonatal conditions.