Charlotte Trenteseaux1, Anh-Thu Gaston1, Audrey Aguesse1, Guillaume Poupeau1, Pierre de Coppet1, Ramaroson Andriantsitohaina1, Jamila Laschet1, Valérie Amarger1, Michel Krempf1, Estelle Nobecourt-Dupuy1, Khadija Ouguerram2. 1. From the UMR 1280 Physiopathologie des Adaptations Nutritionnelles, INRA, Université de Nantes, France (C.T., G.P., P.d.C., V.A., M.K., E.N.-D., K.O.); Centre de Recherche en Nutrition Humaine Ouest, Nantes, France (C.T., A.A., M.K., K.O.); UMR1063 Stress Oxydant et Pathologies Métaboliques, INSERM, Université d'Angers, France (C.T., R.A.); and UMR 1148 Laboratoire de recherche Vasculaire Translationnelle, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Université Paris, France (A.-t.G., J.L.). 2. From the UMR 1280 Physiopathologie des Adaptations Nutritionnelles, INRA, Université de Nantes, France (C.T., G.P., P.d.C., V.A., M.K., E.N.-D., K.O.); Centre de Recherche en Nutrition Humaine Ouest, Nantes, France (C.T., A.A., M.K., K.O.); UMR1063 Stress Oxydant et Pathologies Métaboliques, INSERM, Université d'Angers, France (C.T., R.A.); and UMR 1148 Laboratoire de recherche Vasculaire Translationnelle, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Université Paris, France (A.-t.G., J.L.). Khadija.Ouguerram@univ-nantes.fr.
Abstract
OBJECTIVE: Experimental studies suggest that maternal hypercholesterolemia may be relevant for the early onset of cardiovascular disease in offspring. We investigated the effect of perinatal hypercholesterolemia on the atherosclerosis development in the offspring of apolipoprotein E-deficient mice and the underlying mechanism. APPROACH AND RESULTS: Atherosclerosis and related parameters were studied in adult male or female apolipoprotein E-deficient mice offspring from either normocholesterolemic or hypercholesterolemic mothers and normocholesterolemic fathers. Female born to hypercholesterolemic mothers had more aortic root lesions than female born to normocholesterolemic mothers. Lesions in whole aorta did not differ between groups. Higher trimethylamine-N-oxide levels and Fmo3 hepatic gene expression were higher in female born to hypercholesterolemic mothers offspring compared with female born to normocholesterolemic mothers and male. Trimethylamine-N-oxide levels were correlated with the size of atherosclerotic root lesions. Levels of hepatic cholesterol and gallbladder bile acid were greater in male born to hypercholesterolemic mothers compared with male born to normocholesterolemic mothers. At 18 weeks of age, female born to hypercholesterolemic mothers showed lower hepatic Scarb1 and Cyp7a1 but higher Nr1h4 gene expression compared with female born to normocholesterolemic mothers. Male born to hypercholesterolemic mothers showed an increase in Scarb1 and Ldlr gene expression compared with male born to normocholesterolemic mothers. At 25 weeks of age, female born to hypercholesterolemic mothers had lower Cyp7a1 gene expression compared with female born to normocholesterolemic mothers. DNA methylation of Fmo3, Scarb1, and Ldlr promoter regions was slightly modified and may explain the mRNA expression modulation. CONCLUSIONS: Our findings suggest that maternal hypercholesterolemia may exacerbate the development of atherosclerosis in female offspring by affecting metabolism of trimethylamine-N-oxide and bile acids. These data could be explained by epigenetic alterations.
OBJECTIVE: Experimental studies suggest that maternal hypercholesterolemia may be relevant for the early onset of cardiovascular disease in offspring. We investigated the effect of perinatal hypercholesterolemia on the atherosclerosis development in the offspring of apolipoprotein E-deficientmice and the underlying mechanism. APPROACH AND RESULTS:Atherosclerosis and related parameters were studied in adult male or female apolipoprotein E-deficientmice offspring from either normocholesterolemic or hypercholesterolemic mothers and normocholesterolemic fathers. Female born to hypercholesterolemic mothers had more aortic root lesions than female born to normocholesterolemic mothers. Lesions in whole aorta did not differ between groups. Higher trimethylamine-N-oxide levels and Fmo3 hepatic gene expression were higher in female born to hypercholesterolemic mothers offspring compared with female born to normocholesterolemic mothers and male. Trimethylamine-N-oxide levels were correlated with the size of atherosclerotic root lesions. Levels of hepatic cholesterol and gallbladder bile acid were greater in male born to hypercholesterolemic mothers compared with male born to normocholesterolemic mothers. At 18 weeks of age, female born to hypercholesterolemic mothers showed lower hepatic Scarb1 and Cyp7a1 but higher Nr1h4 gene expression compared with female born to normocholesterolemic mothers. Male born to hypercholesterolemic mothers showed an increase in Scarb1 and Ldlr gene expression compared with male born to normocholesterolemic mothers. At 25 weeks of age, female born to hypercholesterolemic mothers had lower Cyp7a1 gene expression compared with female born to normocholesterolemic mothers. DNA methylation of Fmo3, Scarb1, and Ldlr promoter regions was slightly modified and may explain the mRNA expression modulation. CONCLUSIONS: Our findings suggest that maternal hypercholesterolemia may exacerbate the development of atherosclerosis in female offspring by affecting metabolism of trimethylamine-N-oxide and bile acids. These data could be explained by epigenetic alterations.
Authors: Jerad H Dumolt; Min Ma; Joyce Mathew; Mulchand S Patel; Todd C Rideout Journal: Am J Physiol Endocrinol Metab Date: 2019-08-27 Impact factor: 4.310
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311