title: Activation of the Cardiac Renin-Angiotensin System in High Oxygen-Exposed Newborn Rats: Angiotensin Receptor Blockade Prevents the Developmental Programming of Cardiac Dysfunction.
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.
authors: From the Department of Pediatrics, Sainte-Justine University Hospital Research Center, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada (M.B., A.D., S.B.-B., G.G., M.S., M.-A.L., A.C., A.M.N.); and Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada (P.P., E.L.S.).
authors: Mariane
authors: M
authors: Bertagnolli
authors: From the Department of Pediatrics, Sainte-Justine University Hospital Research Center, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada (M.B., A.D., S.B.-B., G.G., M.S., M.-A.L., A.C., A.M.N.); and Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada (P.P., E.L.S.).
authors: Anne
authors: A
authors: Dios
authors: From the Department of Pediatrics, Sainte-Justine University Hospital Research Center, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada (M.B., A.D., S.B.-B., G.G., M.S., M.-A.L., A.C., A.M.N.); and Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada (P.P., E.L.S.).
authors: Sarah
authors: S
authors: Béland-Bonenfant
authors: From the Department of Pediatrics, Sainte-Justine University Hospital Research Center, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada (M.B., A.D., S.B.-B., G.G., M.S., M.-A.L., A.C., A.M.N.); and Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada (P.P., E.L.S.).
authors: Gabrielle
authors: G
authors: Gascon
authors: From the Department of Pediatrics, Sainte-Justine University Hospital Research Center, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada (M.B., A.D., S.B.-B., G.G., M.S., M.-A.L., A.C., A.M.N.); and Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada (P.P., E.L.S.).
authors: Megan
authors: M
authors: Sutherland
authors: From the Department of Pediatrics, Sainte-Justine University Hospital Research Center, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada (M.B., A.D., S.B.-B., G.G., M.S., M.-A.L., A.C., A.M.N.); and Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada (P.P., E.L.S.).
authors: Marie-Amélie
authors: MA
authors: Lukaszewski
authors: From the Department of Pediatrics, Sainte-Justine University Hospital Research Center, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada (M.B., A.D., S.B.-B., G.G., M.S., M.-A.L., A.C., A.M.N.); and Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada (P.P., E.L.S.).
authors: Anik
authors: A
authors: Cloutier
authors: From the Department of Pediatrics, Sainte-Justine University Hospital Research Center, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada (M.B., A.D., S.B.-B., G.G., M.S., M.-A.L., A.C., A.M.N.); and Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada (P.P., E.L.S.).
authors: Pierre
authors: P
authors: Paradis
authors: From the Department of Pediatrics, Sainte-Justine University Hospital Research Center, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada (M.B., A.D., S.B.-B., G.G., M.S., M.-A.L., A.C., A.M.N.); and Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada (P.P., E.L.S.).
authors: Ernesto L
authors: EL
authors: Schiffrin
authors: From the Department of Pediatrics, Sainte-Justine University Hospital Research Center, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada (M.B., A.D., S.B.-B., G.G., M.S., M.-A.L., A.C., A.M.N.); and Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada (P.P., E.L.S.). anne-monique.nuyt@recherche-ste-justine.qc.ca.
authors: Anne Monique
authors: AM
authors: Nuyt
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000188:drug therapy / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D019808:Losartan / Q000494:pharmacology*; D010100:Oxygen / Q000494:pharmacology*; D011247:Pregnancy; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D012680:Sensitivity and Specificity; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000517:prevention & control*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D017382:Reactive Oxygen Species; D019808:Losartan; D010100:Oxygen
keywords: angiotensin receptors; animal model of human disease; cardiac remodeling; heart development; neonatal oxygen stress