年轻的 Cyp2c70-/- 小鼠血浆胆汁酸升高与心脏压力和炎症同时存在。

IF 3.1 3区 医学 Q1 PEDIATRICS
Hilde D de Vries, Tim R Eijgenraam, Vincent W Bloks, Niels L Mulder, Tim van Zutphen, Herman H W Silljé, Folkert Kuipers, Jan Freark de Boer
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引用次数: 0

摘要

背景:妊娠肝内胆汁淤积症或新生儿胆汁淤积症等导致的高血浆胆汁酸(BA)与心脏异常有关。在这里,我们利用Cyp2c70-/-小鼠血浆中胆汁酸水平的可变性(其胆汁酸组成与人类相似)来研究循环胆汁酸升高对心脏的急性影响:对3周大的Cyp2c70-/-小鼠的心脏进行了RNA测序,这些小鼠缺乏显示新生儿胆汁淤积特征的小鼠特异性BA物种。比较了野生型幼鼠、血浆胆碱酯酶含量低或高的Cyp2c70-/-幼鼠以及围产期接受熊去氧胆酸(UDCA)治疗的母鼠的Cyp2c70-/-幼鼠的心脏转录组:结果:我们发现了1355个基因在Cyp2c70-/-小鼠高血浆胆碱酯酶和低血浆胆碱酯酶的心脏中表达不同,其中富含炎症过程。引人注目的是,其中 1053 个基因(78%)在经 UDCA 处理的母鼠幼崽心脏中的表达趋于正常。此外,645个心脏基因与血浆BAs密切相关,其中172个基因与心血管疾病有关:结论:血浆生物胆碱酯酶升高会改变小鼠心脏的基因表达谱,并与人类的生物胆碱酯酶谱相似,从而揭示了心脏应激和炎症。我们的研究结果支持了高血浆 BA 会在生命早期诱发心脏并发症的观点:影响:具有类人胆汁酸组成的 Cyp2c70-/- 小鼠表现出新生儿胆汁淤积症的特征,但其肝外后果迄今为止几乎未得到研究。 Cyp2c70-/- 幼鼠血浆胆汁酸升高与心脏应激和炎症同时发生。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Elevated plasma bile acids coincide with cardiac stress and inflammation in young Cyp2c70-/- mice.

Background: High plasma bile acids (BAs), for instance due to intrahepatic cholestasis of pregnancy or neonatal cholestasis, are associated with cardiac abnormalities. Here, we exploited the variability in plasma BA levels in Cyp2c70-/- mice with a human-like BA composition to investigate the acute effects of elevated circulating BAs on the heart.

Methods: RNA sequencing was performed on hearts of 3-week-old Cyp2c70-/- mice lacking mouse-specific BA species that show features of neonatal cholestasis. Cardiac transcriptomes were compared between wild-type pups, Cyp2c70-/- pups with low or high plasma BAs, and Cyp2c70-/- pups from dams that were perinatally treated with ursodeoxycholic acid (UDCA).

Results: We identified 1355 genes that were differentially expressed in hearts of Cyp2c70-/- mice with high versus low plasma BAs with enrichment of inflammatory processes. Strikingly, expression of 1053 (78%) of those genes was normalized in hearts of pups of UDCA-treated dams. Moreover, 645 cardiac genes strongly correlated to plasma BAs, of which 172 genes were associated with cardiovascular disease.

Conclusions: Elevated plasma BAs alter gene expression profiles of hearts of mice with a human-like BA profile, revealing cardiac stress and inflammation. Our findings support the notion that high plasma BAs induce cardiac complications in early life.

Impact: Cyp2c70-/- mice with a human-like bile acid composition show features of neonatal cholestasis but the extrahepatic consequences hereof have so far hardly been addressed Elevated plasma bile acids in Cyp2c70-/- pups coincide with cardiac stress and inflammation Perinatal treatment with UDCA prevents dysregulated cardiac gene expression patterns in Cyp2c70-/- pups.

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来源期刊
Pediatric Research
Pediatric Research 医学-小儿科
CiteScore
6.80
自引率
5.60%
发文量
473
审稿时长
3-8 weeks
期刊介绍: Pediatric Research publishes original papers, invited reviews, and commentaries on the etiologies of children''s diseases and disorders of development, extending from molecular biology to epidemiology. Use of model organisms and in vitro techniques relevant to developmental biology and medicine are acceptable, as are translational human studies
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