Increased susceptibility of HIF-1 alpha heterozygous-null mice to cardiovascular malformations associated with maternal diabetes

0395068 - BTÚ 2014 RIV GB eng J - Článek v odborném periodiku
Bohuslavová, Romana - Škvorová, Lada - Sedmera, David - Semenza, G.L. - Pavlínková, Gabriela
Increased susceptibility of HIF-1 alpha heterozygous-null mice to cardiovascular malformations associated with maternal diabetes.
Journal of Molecular and Cellular Cardiology. Roč. 60, Jul (2013), s. 129-141. ISSN 0022-2828. E-ISSN 1095-8584
Grant CEP: GA ČR GA301/09/0117; GA ČR(CZ) GAP302/11/1308
Výzkumný záměr: CEZ:AV0Z50520701
Institucionální podpora: RVO:67985823
Klíčová slova: Diabetic embryopathy * Heart defect * Hypoxia-inducible factor 1 alpha
Kód oboru RIV: EB - Genetika a molekulární biologie; FA - Kardiovaskulární nemoci vč. kardiochirurgie (FGU-C)
Impakt faktor: 5.218, rok: 2013

Cardiovascular malformations are the most common manifestation of diabetic embryopathy. The molecular mechanisms underlying the teratogenic effect of maternal diabetes have not been fully elucidated. Using genome-wide expression profiling, we previously demonstrated that exposure to maternal diabetes resulted in dysregulation of the hypoxia-inducible factor 1 (HIF-1) pathway in the developing embryo. We thus considered a possible link between HIF-1-regulated pathways and the development of congenital malformations. HIF-1 alpha heterozygous-null (Hif1a(+/-)) and wild type (Wt) littermate embryos were exposed to the intrauterine environment of a diabetic mother to analyze the frequency and morphology of congenital defects, and assess gene expression changes in Wt and Hif1a(+/-) embryos. We observed a decreased number of embryos per litter and an increased incidence of heart malformations, including atrioventricular septal defects and reduced myocardial mass, in diabetes-exposed Hif1a(+/-) embryos as compared to Wt embryos. We also detected significant differences in the expression of key cardiac transcription factors, including Nkx2.5, Tbx5, and Mef2C, in diabetes-exposed Hif1a(+/-) embryonic hearts compared to Wt littermates. Thus, partial global HIF-1 alpha deficiency alters gene expression in the developing heart and increases susceptibility to congenital defects in a mouse model of diabetic pregnancy. (C) 2013 Elsevier Ltd. All rights reserved.
Trvalý link: http://hdl.handle.net/11104/0223222