Objective

Heart disease risk can be programmed by intrauterine exposure to obesity. Dysregulating key transcription factors in cardiac progenitors can cause subsequent adult-onset heart disease. Here, we investigated the transcriptional pathways altered in the embryonic heart and linked to heart disease risk in offspring exposed to obesity during pregnancy.

Methods

Female mice were fed an obesogenic diet and mated with males fed a control diet. Heart function and genome-wide gene expression were analyzed in adult offspring born to obese and lean mice at baseline and in response to stress. Cross-referencing with genes dysregulated genome-wide in cardiac progenitors from embryos of obese mice and in human fetal hearts revealed the transcriptional events associated with adult-onset heart disease susceptibility.

Results

We found that adult mice born to obese mothers develop mild heart dysfunction consistent with early stages of disease. Accordingly, hearts of these mice dysregulated genes controlling extracellular matrix remodeling, metabolism, and TGF-β signaling, known to control heart disease progression. Such pathways were dysregulated already in cardiac progenitors in embryos of obese mice. Moreover, in response to cardiovascular stress, the heart of adults born to obese dams developed exacerbated myocardial remodeling and excessively activated regulators of cell-extracellular matrix interaction but failed to activate metabolic regulators. Expression of developmentally regulated genes was altered in cardiac progenitors of embryos of obese mice and in human hearts of fetuses of obese donors. Accordingly, the levels of Nkx2-5, a key regulator of heart development, inversely correlated with maternal body weight in mice. Furthermore Nkx2-5 target genes were dysregulated in cardiac progenitors and persistently in adult hearts born to obese mice, and in human hearts from pregnancies affected by obesity.

Conclusions

Obesity during pregnancy alters NKX2-5-controlled transcription in differentiating cardiac progenitors and persistently in the adult heart, poising the adult heart to dysregulated stress responses.

中文翻译：

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孕产妇肥胖持续改变心脏祖基因表达并编程成人心脏病易感性

客观的

心脏病风险可以通过宫内暴露于肥胖来编程。心脏祖细胞中关键转录因子的失调可导致随后的成人心脏病。在这里，我们研究了胚胎心脏中改变的转录通路，这些通路与怀孕期间暴露于肥胖的后代的心脏病风险有关。

方法

雌性小鼠被喂食致肥饮食，并与喂食对照饮食的雄性交配。对肥胖和瘦小鼠在基线和应激反应下出生的成年后代的心脏功能和全基因组基因表达进行了分析。与来自肥胖小鼠胚胎和人类胎儿心脏的心脏祖细胞中全基因组失调基因的交叉引用揭示了与成人心脏病易感性相关的转录事件。

结果

我们发现肥胖母亲所生的成年小鼠会出现与疾病早期阶段一致的轻度心脏功能障碍。因此，这些小鼠的心脏控制细胞外基质重塑、代谢和 TGF-β 信号传导的基因失调，已知这些基因控制心脏病的进展。这些通路在肥胖小鼠胚胎的心脏祖细胞中已经失调。此外，为了应对心血管压力，肥胖母猪所生的成年人的心脏会出现心肌重构加剧和细胞-细胞外基质相互作用的过度激活调节因子，但未能激活代谢调节因子。在肥胖小鼠胚胎的心脏祖细胞和肥胖供体胎儿的人类心脏中，发育调节基因的表达发生了改变。因此，Nkx2-5的水平是心脏发育的关键调节因子，与小鼠的母体体重呈负相关。此外，Nkx2-5 靶基因在心脏祖细胞中失调，并且在肥胖小鼠出生的成年心脏中以及在受肥胖影响的妊娠中的人类心脏中持续失调。

结论

怀孕期间的肥胖改变了分化心脏祖细胞中 NKX2-5 控制的转录，并持续在成人心脏中，使成人心脏处于失调的压力反应中。