Autophagy is involved in high glucose-induced heart tube malformation

Both pre-gestational and gestational diabetes have an adverse impact on heart development, but little is known about the influence on the early stage of heart tube formation. Using early gastrulating chick embryos, we investigated the influence of high glucose on the process of heart tube formation, specifically during the primary heart field phase. We demonstrated that high-glucose exposure resulted in 3 types of heart tube malformation: 1) ventricular hypertrophy, 2) ventricular hypertrophy with dextrocardia and 3) ventricular hypertrophy and dextrocardia with the fusion anomaly of a bilateral primary heart tube. Next, we found that these malformation phenotypes of heart tubes might mainly originate from the migratory anomaly of gastrulating precardiac mesoderm cells rather than cell proliferation in the developmental process of bilateral primary heart field primordia. The treatment of rapamycin (RAPA), an autophagy inducer, led to a similar heart tube malformation phenotype as high glucose. Additionally, high-glucose exposure promoted the expression of the key autophagy protein LC3B in early chick tissue. Atg7 is strongly expressed in the fusion site of bilateral primary heart tubes. All of these data imply that autophagy could be involved in the process of high-glucose-induced malformation of the heart tube.

孕前糖尿病（pre-gestational diabetes）与妊娠期糖尿病（gestational diabetes）均会对心脏发育造成不良影响，但目前学界对二者在心管形成早期阶段的影响仍知之甚少。本研究以早期原肠胚期鸡胚为实验模型，探究了高糖环境在原发心野（primary heart field）阶段对心管形成过程的作用。研究证实，高糖暴露可诱导出三类心管畸形表型：1）心室肥大；2）合并右位心的心室肥大；3）伴双侧原发心管融合异常的心室肥大与右位心。进一步分析发现，此类心管畸形主要源于原肠期心脏前体中胚层细胞的迁移异常，而非双侧原发心野原基发育过程中的细胞增殖异常。自噬诱导剂雷帕霉素（rapamycin）的处理，可诱导出与高糖暴露一致的心管畸形表型。此外，高糖暴露可上调鸡胚早期组织中自噬关键蛋白LC3B的表达。自噬相关基因7（Atg7）在双侧原发心管的融合位点呈现高表达。上述所有实验数据均表明，自噬可能参与了高糖诱导的心管畸形发生过程。