围产期高胆固醇血症通过改变氧化三甲胺和胆汁酸的代谢加重子代动脉粥样硬化病变。
Perinatal Hypercholesterolemia Exacerbates Atherosclerosis Lesions in Offspring by Altering Metabolism of Trimethylamine-N-Oxide and Bile Acids.
作者信息
Trenteseaux Charlotte, Gaston Anh-Thu, Aguesse Audrey, Poupeau Guillaume, de Coppet Pierre, Andriantsitohaina Ramaroson, Laschet Jamila, Amarger Valérie, Krempf Michel, Nobecourt-Dupuy Estelle, Ouguerram Khadija
机构信息
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.).
出版信息
Arterioscler Thromb Vasc Biol. 2017 Nov;37(11):2053-2063. doi: 10.1161/ATVBAHA.117.309923. Epub 2017 Sep 21.
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 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 and but higher gene expression compared with female born to normocholesterolemic mothers. Male born to hypercholesterolemic mothers showed an increase in and gene expression compared with male born to normocholesterolemic mothers. At 25 weeks of age, female born to hypercholesterolemic mothers had lower gene expression compared with female born to normocholesterolemic mothers. DNA methylation of , and 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.
目的
实验研究表明，母体高胆固醇血症可能与后代心血管疾病的早期发作有关。我们研究了围产期高胆固醇血症对载脂蛋白E缺乏小鼠后代动脉粥样硬化发展的影响及其潜在机制。
方法与结果
对成年雄性或雌性载脂蛋白E缺乏小鼠的后代进行研究，这些后代的母亲分别为正常胆固醇血症或高胆固醇血症，父亲为正常胆固醇血症。高胆固醇血症母亲所生的雌性后代比正常胆固醇血症母亲所生的雌性后代有更多的主动脉根部病变。各组全主动脉病变无差异。与正常胆固醇血症母亲所生的雌性后代和雄性后代相比，高胆固醇血症母亲所生的雌性后代的三甲胺-N-氧化物水平和肝脏基因表达更高。三甲胺-N-氧化物水平与动脉粥样硬化根部病变大小相关。与正常胆固醇血症母亲所生的雄性后代相比，高胆固醇血症母亲所生的雄性后代肝脏胆固醇和胆囊胆汁酸水平更高。在18周龄时，与正常胆固醇血症母亲所生的雌性后代相比，高胆固醇血症母亲所生的雌性后代肝脏基因表达较低，但基因表达较高。与正常胆固醇血症母亲所生的雄性后代相比，高胆固醇血症母亲所生的雄性后代基因表达增加。在25周龄时，与正常胆固醇血症母亲所生的雌性后代相比，高胆固醇血症母亲所生的雌性后代基因表达较低。、和启动子区域的DNA甲基化略有改变，可能解释了mRNA表达的调节。
结论
我们的研究结果表明，母体高胆固醇血症可能通过影响三甲胺-N-氧化物和胆汁酸的代谢，加剧雌性后代动脉粥样硬化的发展。这些数据可以用表观遗传改变来解释。
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