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首页> 外文期刊>Cellular Physiology and Biochemistry >AMP-Activated Protein Kinase α1 Regulates Cardiac Gap Junction Protein Connexin 43 and Electrical Remodeling Following Pressure Overload
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AMP-Activated Protein Kinase α1 Regulates Cardiac Gap Junction Protein Connexin 43 and Electrical Remodeling Following Pressure Overload

机译：AMP激活的蛋白激酶α1调节心脏间隙连接蛋白连接蛋白43和压力超负荷后的电重构

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Background/Aims: Adenosine 5'-monophosphate (AMP)-activated protein kinase (Ampk) modulates a wide array of cellular functions and regulates various ion channels and transporters. In failing human hearts an increased Ampkα1 activity was observed. The present study aimed to uncover the impact of Ampkα1 on cardiac electrical remodeling. Methods: Gene-targeted mice lacking functional Ampkα1 (Ampkα1-/-) and corresponding wild-type mice were exposed to pressure overload by “transverse aortic constriction” (TAC). In vivo electrophysiology was performed with a single catheter technique, myocardial conduction velocities and conduction characteristics investigated in isolated hearts, transcript levels quantified by RT-PCR and protein abundance determined by Western blotting. Moreover, connexin 43 (Cx43) was expressed in Xenopus oocytes with or without coexpression of wild-type or mutant AMPK and Cx43 protein abundance quantified utilizing confocal microscopy. Results: TAC treatment increased Ampkα1 protein expression in cardiac tissue from wild-type mice. TAC further increased left ventricular conduction inhomogeneity and triggered conduction blocks, effects blunted in the Ampkα1-/- mice. TAC treatment decreased Cx43 protein abundance in cardiac tissue, an effect significantly blunted in the Ampkα1-/- mice. TAC treatment did not modify Cx43 mRNA levels but increased ubiquitination of Cx43 protein, an effect mitigated by Ampkα1 deficiency. As shown in Xenopus oocytes, Cx43 cell membrane protein abundance was significantly downregulated by wild-type AMPKWT and constitutively active AMPKγR70Q, but not by catalytically inactive AMPKαK45R. Conclusion: Ampkα1 stimulates ubiquitination of the gap junction protein Cx43, thereby contributing to gap junction remodeling following pressure overload.
机译：背景/目的：5'-单磷酸腺苷（AMP）激活的蛋白激酶（Ampk）调节多种细胞功能，并调节各种离子通道和转运蛋白。在人的心脏衰竭中，观察到Ampkα1活性增加。本研究旨在揭示Ampkα1对心脏电重构的影响。方法：通过“主动脉缩窄”（TAC）使缺乏功能性Ampkα1（Ampkα1-/-）的基因靶向小鼠和相应的野生型小鼠承受压力超负荷。用单导管技术进行体内电生理学，研究离体心脏的心肌传导速度和传导特性，RT-PCR定量转录水平，Western印迹法测定蛋白质丰度。此外，连接蛋白43（Cx43）在具有或不具有野生型或突变型AMPK的共表达的非洲爪蟾卵母细胞中表达，并利用共聚焦显微镜定量了Cx43蛋白的丰度。结果：TAC处理可提高野生型小鼠心脏组织中Ampkα1蛋白的表达。 TAC进一步增加了左心室传导不均匀性并触发了传导阻滞，这在Ampkα1-/-小鼠中的作用减弱。 TAC处理可降低心脏组织中Cx43蛋白的丰度，而在Ampkα1-/-小鼠中这种作用明显减弱。 TAC治疗不会改变Cx43 mRNA的水平，但会增加Cx43蛋白的泛素化作用，而Ampkα1缺乏会减轻这种作用。如非洲爪蟾卵母细胞中所示，野生型AMPK WT 和组成型活性AMPK γR70Q显着下调Cx43细胞膜蛋白的丰度，而不是催化无活性的AMPK αK45R 。结论：Ampkα1刺激间隙连接蛋白Cx43的泛素化，从而促进压力过载后间隙连接的重塑。

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