Glucocorticoid effects on the programming of AT1b angiotensin receptor gene methylation and expression in the rat.
Glucocorticoid effects on the programming of AT1b angiotensin receptor gene methylation and expression in the rat.
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DOI：
10.1371/journal.pone.0009237
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发表时间：
2010-02-16
期刊：
影响因子：
3.7
通讯作者：
Clark AJ
中科院分区：
文献类型：
--
作者：
Bogdarina I;Haase A;Langley-Evans S;Clark AJ
怀孕期间的不良事件可能会“规划”后代，使其日后患上心血管疾病和高血压。在此之前，使用程序性高血压的啮齿动物模型，我们已经证明了在这个过程中的作用，肾素-血管紧张素系统。最近，我们发现母亲低蛋白饮食导致At 1b血管紧张素受体启动子甲基化不足和该基因在后代肾上腺中的早期过度表达。在这里，我们调查的假设，母体糖皮质激素调节胎儿DNA甲基化和基因表达的影响。我们研究了用11β-羟化酶抑制剂甲吡酮治疗大鼠母体是否可以预防我们观察到的表观遗传和基因表达变化。正如我们先前观察到的，在怀孕期间接受低蛋白饮食的母亲的后代显示肾上腺Agtr 1b甲基化减少和肾上腺基因表达增加。在怀孕的前14天用甲吡酮治疗母亲逆转了这些变化，并防止了后代在4周龄时出现高血压。作为程序性高血压非特异性效应的对照，我们研究了从妊娠第15天开始接受地塞米松治疗的母亲的后代，结果表明，虽然他们的血压升高，但他们没有表现出任何Agtr 1b甲基化或基因表达增加的证据。我们的结论是，母体糖皮质激素在怀孕早期可能会引起甲基化和表达的Agtr 1b基因的变化，因为这些明显逆转的11 β-羟化酶抑制剂。然而，在妊娠后期，地塞米松的匡威作用无法证明，这可能反映了这种糖皮质激素的替代机制或阶段特异性影响。
Adverse events in pregnancy may ‘programme’ offspring for the later development of cardiovascular disease and hypertension. Previously, using a rodent model of programmed hypertension we have demonstrated the role of the renin-angiotensin system in this process. More recently we showed that a maternal low protein diet resulted in undermethylation of the At1b angiotensin receptor promoter and the early overexpression of this gene in the adrenal of offspring. Here, we investigate the hypothesis that maternal glucocorticoid modulates this effect on fetal DNA methylation and gene expression. We investigated whether treatment of rat dams with the 11β-hydroxylase inhibitor metyrapone, could prevent the epigenetic and gene expression changes we observed. Offspring of mothers subjected to a low protein diet in pregnancy showed reduced adrenal Agtr1b methylation and increased adrenal gene expression as we observed previously. Treatment of mothers with metyrapone for the first 14 days of pregnancy reversed these changes and prevented the appearance of hypertension in the offspring at 4 weeks of age. As a control for non-specific effects of programmed hypertension we studied offspring of mothers treated with dexamethasone from day 15 of pregnancy and showed that, whilst they had raised blood pressure, they failed to show any evidence of Agtr1b methylation or increase in gene expression. We conclude that maternal glucocorticoid in early pregnancy may induce changes in methylation and expression of the Agtr1b gene as these are clearly reversed by an 11 beta-hydroxylase inhibitor. However in later pregnancy a converse effect with dexamethasone could not be demonstrated and this may reflect either an alternative mechanism of this glucocorticoid or a stage-specific influence.
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影响因子：
8.3
作者：
Gardner, DS;Jackson, AA;Langley-Evans, SC
通讯作者：
Langley-Evans, SC
影响因子：
8.3
作者：
Jöhren, O;Golsch, C;Dominiak, P
通讯作者：
Dominiak, P
在怀孕期间喂养蛋白质限制饮食的大鼠后代中肝糖皮质激素受体的表观遗传调节改变的诱导表明，DNA甲基转移酶-1表达降低与DNA甲基化受损和组蛋白修饰的变化有关。
影响因子：
3.6
作者：
Lillycrop, Karen A.;Slater-Jefferies, Jo L.;Hanson, Mark A.;Godfrey, Keith M.;Jackson, Alan A.;Burdge, Graham C.
通讯作者：
Burdge, Graham C.
影响因子：
4.2
作者：
Lillycrop, KA;Phillips, ES;Burdge, GC
通讯作者：
Burdge, GC
影响因子：
7.7
作者：
Law, CM;Egger, P;Barker, DJP
通讯作者：
Barker, DJP