Serine/Threonine-Protein Kinase 3 Facilitates Myocardial Repair After Cardiac Injury Possibly Through the Glycogen Synthase Kinase-3β/β-Catenin Pathway.
Serine/Threonine-Protein Kinase 3 Facilitates Myocardial Repair After Cardiac Injury Possibly Through the Glycogen Synthase Kinase-3β/β-Catenin Pathway.
复制标题
丝氨酸/苏氨酸蛋白激酶3可能通过糖原合成酶激酶3β/β-连环蛋白途径促进心肌损伤后的心肌修复。
DOI：
10.1161/jaha.121.022802
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发表时间：
2021-11-16
影响因子：
5.4
通讯作者：
Wang LS
中科院分区：
文献类型：
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作者：
Li YF;Wei TW;Fan Y;Shan TK;Sun JT;Chen BR;Wang ZM;Gu LF;Yang TT;Liu L;Du C;Ma Y;Wang H;Sun R;Wei YY;Chen F;Guo XJ;Kong XQ;Wang LS
新生儿的心脏在出生后几天内保持其全部的再生能力。利用定量磷蛋白质组学技术，我们发现心肌梗死后，SGK3(丝氨酸/苏氨酸蛋白激酶3)在新生大鼠心脏中高表达并被激活。本研究旨在揭示SGK3在心尖切除或缺血再灌注损伤后对心肌细胞增殖和心脏修复的作用及其相关机制。应用心肌细胞特异性SGK3过表达或基因敲除腺病毒载体检测SGK3对缺氧缺糖/复氧诱导的心肌细胞增殖和凋亡的影响。在活体条件下，应用心肌细胞特异性腺相关病毒9进行功能获得和功能丧失实验，以确定SGK3对心尖切除或缺血/再灌注损伤后心肌细胞增殖和心脏修复的影响。在体外，SGK3的过度表达增加，而SGK3的下调减少，心肌细胞的增殖率。在体内，抑制SGK3的表达缩短了新生小鼠心脏心尖切除后的再生时间窗，而SGK3的过表达显著促进了成年小鼠缺血再灌注损伤后的心肌修复和心功能的恢复。机制上，SGK3通过抑制GSK-3β(糖原合成酶-3β)活性，上调β-连环蛋白表达，促进心脏损伤后心肌细胞再生和心肌修复。SGK3还上调细胞周期促进基因G1/S特异性细胞周期蛋白-D_1、c-myc(细胞-髓细胞瘤病毒癌基因)和CD20(细胞分裂周期20)的表达，但下调细胞周期负调控基因细胞周期蛋白激酶抑制因子P21和细胞周期蛋白激酶抑制因子P27的表达。我们的研究揭示了SGK3在心尖切除或缺血/再灌注损伤后心脏修复中的关键作用，这可能重新打开心肌梗死治疗的新选择。
The neonatal heart maintains its entire regeneration capacity within days after birth. Using quantitative phosphoproteomics technology, we identified that SGK3 (serine/threonine‐protein kinase 3) in the neonatal heart is highly expressed and activated after myocardial infarction. This study aimed to uncover the function and related mechanisms of SGK3 on cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. The effect of SGK3 on proliferation and oxygen glucose deprivation/reoxygenation– induced apoptosis in isolated cardiomyocytes was evaluated using cardiomyocyte‐specific SGK3 overexpression or knockdown adenovirus5 vector. In vivo, gain‐ and loss‐of‐function experiments using cardiomyocyte‐specific adeno‐associated virus 9 were performed to determine the effect of SGK3 in cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. In vitro, overexpression of SGK3 enhanced, whereas knockdown of SGK3 decreased, the cardiomyocyte proliferation ratio. In vivo, inhibiting the expression of SGK3 shortened the time window of cardiac regeneration after apical resection in neonatal mice, and overexpression of SGK3 significantly promoted myocardial repair and cardiac function recovery after ischemia/reperfusion injury in adult mice. Mechanistically, SGK3 promoted cardiomyocyte regeneration and myocardial repair after cardiac injury by inhibiting GSK‐3β (glycogen synthase kinase‐3β) activity and upregulating β‐catenin expression. SGK3 also upregulated the expression of cell cycle promoting genes G1/S‐specific cyclin‐D1, c‐myc (cellular‐myelocytomatosis viral oncogene), and cdc20 (cell division cycle 20), but downregulated the expression of cell cycle negative regulators cyclin kinase inhibitor P 21 and cyclin kinase inhibitor P 27. Our study reveals a key role of SGK3 on cardiac repair after apical resection or ischemia/reperfusion injury, which may reopen a novel therapeutic option for myocardial infarction.