Apelin通过AMPK依赖性通路改善了高糖引起的新生大鼠心肌细胞Cx43下调
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Apelin Ameliorates High Glucose-Induced Downregulation of Connexin 43 via AMPK-Dependent Pathway in Neonatal Rat Cardiomyocytes
背景与目的
糖尿病是一种常见的代谢性疾病，可使心律失常的发生风险增加。研究显示，高血糖可改变缝隙连接蛋白的表达和缝隙连接重构，从而导致心律失常甚至猝死。缝隙连接蛋白43（Cx43）是构成心脏缝隙连接的主要蛋白，发现在高糖时下调，并抑制缝隙连接细胞间通信（GJIC）。此外，apelin是一种有益的脂肪因子，可增加小鼠和人胚胎干细胞中Cx43蛋白的表达。
方 法
本实验通过细胞转染和Western blotting技术观察CX43的表达情况。
结 果
我们发现在高糖时，Cx43蛋白表达降低，GJIC受损，而给予apelin48后可逆转。我们同时发现，apelin增加了正常血糖时的Cx43蛋白表达。实时PCR显示，apelin或高糖+apelin组的Cx43 mRNA在高糖环境下没有显著差异。有趣的是，我们发现在给予AMPK受体激动剂AICAR后，Cx43表达增加。通过siRNA-AMPKα1和siRNA-AMPKα2转染抑制AMPKα后，可消除apelin对Cx43的作用。
结 论
apelin能够减弱高糖诱导的Cx43下调，部分通过AMPK途径改善缝隙连接功能的受损。
原始文献摘要
Li X, Yu L, Gao J, et al. Apelin Ameliorates High Glucose-Induced Downregulation of Connexin 43 via AMPK-Dependent Pathway in Neonatal Rat Cardiomyocytes[J]. Aging & Disease, 2018, 9(1):66-76.
Abstract：
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.
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