Activation of the Cardiac Renin-Angiotensin System in High Oxygen-Exposed Newborn Rats Angiotensin Receptor Blockade Prevents the Developmental Programming of Cardiac Dysfunction

作者：Bertagnolli Mariane; Dios Anne; Beland Bonenfant Sarah; Gascon Gabrielle; Sutherland Megan; Lukaszewski Marie Amelie; Cloutier Anik; Paradis Pierre; Schiffrin Ernesto L; Nuyt Anne Monique^*

来源：Hypertension, 2016, 67(4): 774-782.

DOI：10.1161/HYPERTENSIONAHA.115.06745

• angiotensin receptors
• animal model of human disease
• cardiac remodeling
• heart development
• neonatal oxygen stress

Newborn rats exposed to high oxygen (O-2), 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 O-2-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 O-2 exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague-Dawley newborn rats were kept with their mother in 80% O-2 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 O-2 exposure), P5, P10 (end of O-2), 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 O-2 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 O-2-exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-/SMAD3 pathway, and upregulation of cardiac angiotensin-converting enzyme 2. In conclusion, short-term Ang II blockade during neonatal high O-2 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.

• 出版日期2016-4
• 单位河北医科大学; McGill