HAND1 loss-of-function within the embryonic myocardium reveals survivable congenital cardiac defects and adult heart failure
HAND1 loss-of-function within the embryonic myocardium reveals survivable congenital cardiac defects and adult heart failure
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DOI：
10.1093/cvr/cvz182
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发表时间：
2020-03-01
影响因子：
10.8
通讯作者：
Firulli, Anthony B.
中科院分区：
文献类型：
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作者：
Firulli, Beth A.;George, Rajani M.;Firulli, Anthony B.
目的 探讨碱性螺旋-环-螺旋（bHLH）转录因子HAND1在胚胎和成体心肌中的作用。方法与结果Hand1在胚胎（E）9.5-13.5天期间在左心室（LV）和心肌袖带的心肌细胞中表达。 Hand 基因剂量在心室形态中起着重要作用，Hand1 对先天性心脏缺陷的贡献需要进一步研究。使用 Nkx2.5 敲入 Cre (Nkx2.5(Cre)) 或 α-肌球蛋白重链 Cre (α Mhc-Cre) 驱动程序对 Hand1 进行条件消融。通过独创性途径分析对转录组数据的询问揭示了几种基因调控途径被破坏，包括翻译和心脏肥大相关途径。对胚胎和成人心脏进行组织学、功能和分子分析。 Hand1 的心肌缺失会导致形态缺陷，包括心脏传导系统缺陷、可存活的室间隔缺损和左室乳头肌 (PM) 异常。由此产生的 Hand1 条件突变体以孟德尔频率诞生；但心脏发育过程中获得的形态学改变导致小鼠出现舒张性心力衰竭。结论总的来说，这些数据表明，HAND1 有助于胚胎发生过程中心肌细胞的形态发生模式和成熟，尽管可以存活，但表明 Hand1 在发育中的传导系统和 PM 发育中发挥着作用。
Aims To examine the role of the basic Helix-loop-Helix (bHLH) transcription factor HAND1 in embryonic and adult myocardium.Methods and results Hand1 is expressed within the cardiomyocytes of the left ventricle (LV) and myocardial cuff between embryonic days (E) 9.5-13.5. Hand gene dosage plays an important role in ventricular morphology and the contribution of Hand1 to congenital heart defects requires further interrogation. Conditional ablation of Hand1 was carried out using either Nkx2.5 knockin Cre (Nkx2.5(Cre)) or alpha-myosin heavy chain Cre (alpha Mhc-Cre) driver. Interrogation of transcriptome data via ingenuity pathway analysis reveals several gene regulatory pathways disrupted including translation and cardiac hypertrophy-related pathways. Embryo and adult hearts were subjected to histological, functional, and molecular analyses. Myocardial deletion of Hand1 results in morphological defects that include cardiac conduction system defects, survivable interventricular septal defects, and abnormal LV papillary muscles (PMs). Resulting Hand1 conditional mutants are born at Mendelian frequencies; but the morphological alterations acquired during cardiac development result in, the mice developing diastolic heart failure.Conclusion Collectively, these data reveal that HAND1 contributes to the morphogenic patterning and maturation of cardiomyocytes during embryogenesis and although survivable, indicates a role for Hand1 within the developing conduction system and PM development.