title: All-trans retinoic acid stimulates gene expression of the cardioprotective natriuretic peptide system and prevents fibrosis and apoptosis in cardiomyocytes of obese ob/ob mice.
abstract: In hypertensive rodents, retinoic acid (RA) prevents adverse cardiac remodelling and improves myocardial infarction outcome, but its role in obesity-related changes of cardiac tissue are unclear. We hypothesized that all-trans RA (ATRA) treatment will improve the cardioprotective oxytocin-natriuretic peptides (OT-NP) system, preventing apoptosis and collagen accumulation in hearts of ob/ob mice, a mouse model of obesity and insulin resistance. Female 9-week-old B6.V-Lep/J ob/ob mice (n = 16) were divided into 2 groups: 1 group (n = 8) treated with 100 μg of ATRA dissolved in 100 μL of corn oil (vehicle) delivered daily (∼2 μg·g body weight(-1)·day(-1)) by stomach intubation for 16 days, and 1 group (n = 8) that received the vehicle alone. A group of nonobese littermate mice (n = 9) served as controls. Ob/ob mice exhibited obesity, hyperglycaemia, and downregulation of the cardiac OT-NP system, including the mRNA for the transcription factor GATA4, OT receptor and brain NP, and the protein expression for endothelial nitric oxide synthase. Hearts from ob/ob mice also demonstrated increased apoptosis and collagen accumulation. ATRA treatment induced weight loss and decreased adipocytes diameter in the visceral fat, thus reducing visceral obesity, which is associated with a high risk for cardiovascular disease. RA treatment was associated with a reduction in hyperglycemia and a normalization of the OT-NP system's expression in the hearts of ob/ob mice. Furthermore, ATRA treatment prevented apoptosis and collagen accumulation in hearts of ob/ob mice. The present study indicates that ATRA treatment was effective in restoring the cardioprotective OT-NP system and in preventing abnormal cardiac remodelling in the ob/ob mice.
authors.affiliation: a Laboratory of Nutrition and Cancer, Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Québec, Canada.
authors.forename: Daniel-Constantin
authors.initials: DC
authors.lastname: Manolescu
authors.forename: Marek
authors.initials: M
authors.lastname: Jankowski
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Danalache
authors.forename: Donghao
authors.initials: D
authors.lastname: Wang
authors.forename: Tom L
authors.initials: TL
authors.lastname: Broderick
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Chiasson
authors.forename: Jolanta
authors.initials: J
authors.lastname: Gutkowska
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D005260:Female; D005355:Fibrosis / Q000517:prevention & control; D005786:Gene Expression Regulation; D051379:Mice; D008820:Mice, Obese; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D045265:Natriuretic Peptides / Q000235:genetics*; D009765:Obesity / Q000378:metabolism* / Q000473:pathology*; D014212:Tretinoin / Q000502:physiology*
chemical_list: D045265:Natriuretic Peptides; D014212:Tretinoin
keywords: acide rétinoïque; apoptose; apoptosis; cardiac fibrosis; cardioprotection; fibrose cardiaque; glycaemia; glycémie; gras viscéral; lipolyse; lipolysis; natriuretic peptides; ob/ob mice; ocytocine; oxytocin; peptide natriurétique; retinoic acid; souris ob/ob; visceral fat