Inhibition of SENP2-mediated Akt deSUMOylation promotes cardiac regeneration via activating Akt pathway
Inhibition of SENP2-mediated Akt deSUMOylation promotes cardiac regeneration via activating Akt pathway
复制标题
抑制 SENP2 介导的 Akt 去SUMO化通过激活 Akt 通路促进心脏再生
DOI：
10.1042/cs20201408
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发表时间：
2021-03-01
期刊：
影响因子：
6
通讯作者：
Bin, Jianping
中科院分区：
文献类型：
--
作者：
Chen, Yijin;Xu, Tong;Bin, Jianping
小泛素样修饰物（SUMO）的翻译后修饰（PTM）是细胞增殖的关键调节剂，可以很容易地被SUMO特异性蛋白酶（SENPs）家族逆转，使SUMO化成为开发促进心脏再生反应的新治疗策略的理想调节机制。然而，SUMOylation在心脏再生中的作用尚不清楚。在本研究中，我们评估了靶向蛋白激酶B (Akt) SUMOylation是否可以促进心脏再生。定量PCR和Western blotting结果显示，小泛素样修饰物特异性蛋白酶2 （SENP2）在出生后心脏发育过程中上调。SENP2缺乏促进P7和成人心肌细胞（CM）在体外和体内的去分化和增殖。SENP2缺失小鼠心肌梗死后心功能因CM增殖和血管生成而改善。从机制上讲，SENP2的缺失上调了Akt SUMOylation水平，增加了Akt激酶活性，导致GSK3？从而促进CM增殖和血管生成。综上所述，抑制senp2介导的Akt deSUMOylation通过激活Akt通路促进CM分化和增殖。我们的研究结果为SUMOylation在心脏再生中的作用提供了新的见解。
Post-translational modification (PTM) by small ubiquitin-like modifier (SUMO) is a key regulator of cell proliferation and can be readily reversed by a family of SUMO-specific proteases (SENPs), making SUMOylation an ideal regulatory mechanism for developing novel therapeutic strategies for promoting a cardiac regenerative response. However, the role of SUMOylation in cardiac regeneration remains unknown. In the present study, we assessed whether targeting protein kinase B (Akt) SUMOylation can promote cardiac regeneration. Quantitative PCR and Western blotting results showed that small ubiquitin-like modifier-specific protease 2 (SENP2) is up-regulated during postnatal heart development. SENP2 deficiency promoted P7 and adult cardiomyocyte (CM) dedifferentiation and proliferation both in vitro and in vivo. Mice with SENP2 deficiency exhibited improved cardiac function after MI due to CM proliferation and angiogenesis. Mechanistically, the loss of SENP2 up-regulated Akt SUMOylation levels and increased Akt kinase activity, leading to a decrease in GSK3? levels and subsequently promoting CM proliferation and angiogenesis. In summary, inhibition of SENP2-mediated Akt deSUMOylation promotes CM differentiation and proliferation by activating the Akt pathway. Our results provide new insights into the role of SUMOylation in cardiac regeneration.