Abstract：
Congenital heart disease (CHD) is a type of major defect that occurs during embryonic development. Although significant advances have been made in the treatment of CHD, its etiology and molecular mechanism remain unclear. To identify the critical role of SUMOylation in cardiac development, we generated SENP3 knockout mice and showed that SENP3 knockout mice die on embryonic day 8.5 with an open neural tube and reversed left-right cardiac asymmetry. Moreover, SENP3 knockout promoted apoptosis and senescence of H9C2 cells. Further studies showed that Nodal, a critical gene that forms left-right asymmetry, is regulated by SENP3 and that SENP3 regulates cell apoptosis and senescence in a Nodal-dependent manner. Furthermore, Nodal was hyper-SUMOylated after SENP3 knockout, and SUMOylation of Nodal inhibited its ubiquitination and ubiquitin-proteasome degradation pathway. Nodal overexpression enhanced cell apoptosis and senescence; however, the mutation at the SUMOylation site of Nodal reversed its effect on the apoptosis and senescence of H9C2 cells. More importantly, the SENP3-Nodal axis regulates cell senescence by inducing cell autophagy. These results suggest that the SENP3-Nodal signaling axis regulates cardiac senescence-autophagy homeostasis, which in turn affects cardiac development and results in the occurrence of CHD.
摘要：
先天性心脏病（CHD）是胚胎发育过程中发生的一种主要缺陷。尽管在冠心病的治疗方面取得了重大进展，其病因和分子机制尚不清楚。为了确定SUMO化在心脏发育中的关键作用，我们产生了SENP3基因敲除小鼠,并显示SENP3基因敲除小鼠在胚胎第8.5天死亡,其神经管开放并逆转了左右心脏不对称.此外，SENP3敲除促进H9C2细胞凋亡和衰老。进一步的研究表明，节点，形成左右不对称的关键基因，受SENP3调节，SENP3以Nodal依赖性方式调节细胞凋亡和衰老。此外，SENP3敲除后，Nodal被高度SUMO化，Nodal的SUMO化抑制了其泛素化和泛素-蛋白酶体降解途径。Nodal过表达增强了细胞凋亡和衰老；然而，NodalSUMO化位点的突变逆转了其对H9C2细胞凋亡和衰老的影响。更重要的是,SENP3-Nodal轴通过诱导细胞自噬调节细胞衰老。这些结果表明SENP3-Nodal信号轴调节心脏衰老-自噬稳态，进而影响心脏发育并导致CHD的发生。
