Atrial Fibrillation Activates AMP-Dependent Protein Kinase and its Regulation of Cellular Calcium Handling Potential Role in Metabolic Adaptation and Prevention of Progression
Atrial Fibrillation Activates AMP-Dependent Protein Kinase and its Regulation of Cellular Calcium Handling Potential Role in Metabolic Adaptation and Prevention of Progression
复制标题
DOI：
10.1016/j.jacc.2015.04.056
复制
发表时间：
2015-07-07
影响因子：
24
通讯作者：
Nattel, Stanley
中科院分区：
文献类型：
--
作者：
Harada, Masahide;Tadevosyan, Artavazd;Nattel, Stanley
心房颤动（AF）与代谢应激有关，代谢应激可激活腺苷一磷酸调节蛋白激酶（AMPK）。本研究旨在检测AMPK对AF和相关代谢应激的反应，沿着心房心肌细胞钙离子（Ca 2+）处理的结果。AMPK磷酸化和AMPK与Ca 2+处理蛋白的关联进行了评估，通过免疫印迹和immunoprecipitation.RESULTS钙通道振幅和CS降低4分钟糖酵解抑制（GI），但在8分钟恢复到基线，表明细胞适应代谢应激，可能是由于AMPK激活。GI增加AMPK激活磷酸化，AMPK抑制剂，化合物C（CompC），取消适应CaT和CS GI。AMPK激活剂5-氨基咪唑-4-甲酰胺核苷酸（AICAR）增加CaT振幅和CS，恢复CompC诱导的CaT和CS降低。在电压钳条件下，CompC可降低犬心肌细胞L型钙通道电流（I-Ca，I-L），沿着I-Ca，I-L触发的CaT幅度和肌浆网（SR）Ca ~（2+）含量，抑制人心肌细胞CaT和伊卡，L。基于小干扰核糖核酸的AMPK敲低降低新生大鼠心肌细胞CaT振幅L型钙通道a亚单位与AMPKa共免疫沉淀。心房AMPK激活磷酸化增强1周的电维持AF犬;分数AMPK磷酸化增加阵发性AF和减少长期持续性AF patients.CONCLUSIONS AMPK激活代谢应激和AF，并有助于维持心房I-Ca，I-L，Ca 2+处理的完整性，和细胞收缩性。AMPK参与心房对AF相关代谢应激的代偿反应，AF相关代谢反应可能是一个有趣的新的治疗靶点。(C)2015年由美国心脏病学会基金会。
BACKGROUND Atrial fibrillation (AF) is associated with metabolic stress, which activates adenosine monophosphate-regulated protein kinase (AMPK).OBJECTIVES This study sought to examine AMPK response to AF and associated metabolic stress, along with consequences for atrial cardiomyocyte Ca2+ handling.METHODS Calcium ion (Ca2+) transients (CaTs) and cell shortening (CS) were measured in dog and human atrial cardiomyocytes. AMPK phosphorylation and AMPK association with Ca2+-handling proteins were evaluated by immunoblotting and immunoprecipitation.RESULTS CaT amplitude and CS decreased at 4-min glycolysis inhibition (GI) but returned to baseline at 8 min, suggesting cellular adaptation to metabolic stress, potentially due to AMPK activation. GI increased AMPK-activating phosphorylation, and an AMPK inhibitor, compound C (CompC), abolished the adaptation of CaT and CS to GI. The AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) increased CaT amplitude and CS, restoring CompC-induced CaT and CS decreases. CompC decreased L-type calcium channel current (I-Ca,I-L), along with I-Ca,I-L-triggered CaT amplitude and sarcoplasmic reticulum (SR) Ca2+ content under voltage clamp conditions in dog cells and suppressed CaT and ICa, L in human cardiomyocytes. Small interfering ribonucleic acid-based AMPK knockdown decreased CaT amplitude in neonatal rat cardiomyocytes. L-type Ca2+ channel a subunits coimmunoprecipitated with AMPKa. Atrial AMPK-activating phosphorylation was enhanced by 1 week of electrically maintained AF in dogs; fractional AMPK phosphorylation was increased in paroxysmal AF and reduced in longstanding persistent AF patients.CONCLUSIONS AMPK is activated by metabolic stress and AF, and helps maintain the intactness of atrial I-Ca,I-L, Ca2+ handling, and cell contractility. AMPK contributes to the atrial compensatory response to AF-related metabolic stress; AF-related metabolic responses may be an interesting new therapeutic target. (C) 2015 by the American College of Cardiology Foundation.