Apelin Ameliorates High Glucose-Induced Downregulation of Connexin 43 via AMPK-Dependent Pathway in Neonatal Rat Cardiomyocytes.
Apelin Ameliorates High Glucose-Induced Downregulation of Connexin 43 via AMPK-Dependent Pathway in Neonatal Rat Cardiomyocytes.
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Apelin 通过 AMPK 依赖性途径改善新生大鼠心肌细胞中高血糖诱导的 Connexin 43 下调
DOI：
10.14336/ad.2017.0426
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发表时间：
2018-03
影响因子：
7.4
通讯作者：
Fu G
中科院分区：
文献类型：
--
作者：
Li X;Yu L;Gao J;Bi X;Zhang J;Xu S;Wang M;Chen M;Qiu F;Fu G
糖尿病是一种常见疾病，发生心律失常的风险越来越高。研究表明，在高血糖状态下，缝隙连接蛋白表达改变和缝隙连接重构是心律失常甚至猝死的高发因素。连接蛋白43(Cx43)是一种形成心脏缝隙连接的主要蛋白质，已发现在高糖条件下表达下调，并抑制缝隙连接细胞间通讯(GJIC)。而Apelin，一种有益的脂肪因子，在心脏分化过程中增加了Cx43蛋白在小鼠和人类胚胎干细胞中的表达。然而，目前尚不清楚Apelin是否影响心肌细胞的GJIC能力。通过Western blotting和染料转移实验，我们发现高糖处理后Cx43蛋白表达降低，GJIC受损，而Apelin处理48h后Cx43蛋白表达降低，而在正常葡萄糖条件下，Apelin使Cx43蛋白表达增加。实时荧光定量聚合酶链式反应显示，在高糖条件下，apelin或高糖及apelin对Cx43基因的表达无明显影响。高糖降低AMPKα的磷酸化水平，而Apelin激活AMPKα。有趣的是，我们发现用AMPK信号激活剂AICAR处理后，Cx43的表达增加。小干扰RNA-AMPKα1和小干扰RNA-AMPKα2介导的AMPKα抑制作用可阻断Apelin对Cx43表达的保护作用。我们的数据表明，apelin减轻了高糖诱导的Cx43下调，并部分通过AMPK途径改善了功能缝隙连接的丢失。
Diabetes Mellitus is a common disorder, with increasing risk of cardiac arrhythmias. Studies have shown that altered connexin expression and gap junction remodeling under hyperglycemia contribute to the high prevalence of cardiac arrhythmias and even sudden death. Connexin 43 (Cx43), a major protein that assembles to form cardiac gap junctions, has been found to be downregulated under high glucose conditions, along with inhibition of gap junctional intercellular communication (GJIC). While, apelin, a beneficial adipokine, increases Cx43 protein expression in mouse and human embryonic stem cells during cardiac differentiation. However, it remains unknown whether apelin influences GJIC capacity in cardiomyocytes. Here, using Western blotting and dye transfer assays, we found that Cx43 protein expression was reduced and GJIC was impaired after treatment with high glucose, which, however, could be abrogated after apelin treatment for 48 h. We also found that apelin increased Cx43 expression under normal glucose. Real-time PCR showed that the Cx43 mRNA was not significantly affected under high glucose conditions in the presence of apelin or high glucose and apelin. High glucose decreased the phosphorylation of AMPKα; however, apelin activated AMPKα. Interestingly, we found that Cx43 expression was increased after treatment with AICAR, an activator of AMPK signaling. AMPKα inhibition mediated with transfection of siRNA-AMPKα1 and siRNA-AMPKα2 abolished the protective effect of apelin on Cx43 expression. Our data suggest that apelin attenuates high glucose-induced Cx43 downregulation and improves the loss of functional gap junctions partly through the AMPK pathway.