title: Differences in cell-type-specific responses to angiotensin II explain cardiac remodeling differences in C57BL/6 mouse substrains.
abstract: Despite indications that hearts from the C57BL/6N and C57BL/6J mouse substrains differ in terms of their contractility and their responses to stress-induced overload, no information is available about the underlying molecular and cellular mechanisms. We tested whether subacute (48 hours) and chronic (14 days) administration of angiotensin II (500 ng/kg per day) had different effects on the left ventricles of male C57BL/6J and C57BL/6N mice. Despite higher blood pressure in C57BL/6J mice, chronic angiotensin II induced fibrosis and increased the left ventricular weight/body weight ratio and cardiac expression of markers of left ventricular hypertrophy to a greater extent in C57BL/6N mice. Subacute angiotensin II affected a greater number of cardiac genes in C57BL/6N than in C57BL/6J mice. Some of the most prominent differences were observed for markers of (1) macrophage activation and M2 polarization, including 2 genes (osteopontin and galectin-3) whose inactivation was reported as sufficient to prevent angiotensin II-induced myocardial fibrosis; and (2) fibroblast activation. These differences were confirmed in macrophage- and fibroblast-enriched populations of cells isolated from the hearts of experimental mice. When testing F2 animals, the amount of connective tissue present after chronic angiotensin II administration did not cosegregate with the inactivation mutation of the nicotinamide nucleotide transhydrogenase gene from C57BL/6J mice, thus discounting its possible contribution to differences in cardiac remodeling. However, expression levels of osteopontin and galectin-3 were cosegregated in hearts from angiotensin II-treated F2 animals and may represent endophenotypes that could facilitate the identification of genetic regulators of the cardiac fibrogenic response to angiotensin II.
authors: From the Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada; and Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
authors: Sophie
authors: S
authors: Cardin
authors: From the Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada; and Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
authors: Marie-Pier
authors: MP
authors: Scott-Boyer
authors: From the Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada; and Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
authors: Samantha
authors: S
authors: Praktiknjo
authors: From the Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada; and Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
authors: Saloua
authors: S
authors: Jeidane
authors: From the Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada; and Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
authors: Sylvie
authors: S
authors: Picard
authors: From the Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada; and Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
authors: Timothy L
authors: TL
authors: Reudelhuber
authors: From the Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada; and Department of Medicine, Université de Montréal, Montréal, Québec, Canada. deschec@ircm.qc.ca.
authors: Christian F
authors: CF
authors: Deschepper
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D037502:Galectin 3 / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D053495:Osteopontin / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D037502:Galectin 3; D053495:Osteopontin; D000804:Angiotensin II
keywords: angiotensin II; endomyocardial fibrosis; genetic; macrophages; polymorphisms; ventricular remodeling