Arrhythmia causes lipid accumulation and reduced glucose uptake
Arrhythmia causes lipid accumulation and reduced glucose uptake
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DOI：
10.1007/s00395-015-0497-2
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发表时间：
2015-07-01
影响因子：
9.5
通讯作者：
Laufs, Ulrich
中科院分区：
文献类型：
--
作者：
Lenski, Matthias;Schleider, Gregor;Laufs, Ulrich
心房颤动（AF）的特征是心房心肌细胞不规则收缩和能量需求增加。本研究的目的是表征心律失常对心肌细胞、小鼠和人左心房心肌葡萄糖和脂肪酸（FA）代谢的影响。与规则起搏相比，新生大鼠心肌细胞的不规则（在相同收缩次数/min下的伪随机变化）起搏诱导较短的动作电位持续时间和有效不应期，并增加舒张期[Ca 2 +]（c）。这与Ca 2 +/钙调素依赖性蛋白激酶II（CaMKII）和AMP激活的蛋白激酶（AMPK）的激活有关。脂肪酸转位酶（FAT/CD 36）的膜表达和C-14-棕榈酸摄取增加，而葡萄糖转运蛋白亚型4（GLUT-4）的膜表达以及H-3-葡萄糖摄取减少。AMPK和CaMKII的抑制阻止了这些由疟疾引起的代谢变化。在自发性房颤的转基因小鼠模型（RacET）中观察到FA代谢的类似改变。与这些发现一致，AF患者的左心房心肌样品与窦性心律患者的匹配样品相比显示CaMKII和AMPK的上调以及FAT/CD 36的膜表达增加，导致脂质积聚。FA代谢的这些变化伴随着GLUT-4的膜表达减少，糖原含量增加和促凋亡蛋白bax的表达增加。心肌细胞的不规则起搏增加舒张期[Ca 2 +]（c）和CaMKII和AMPK的活化，导致脂质蓄积、葡萄糖摄取减少和糖原合成增加。这些代谢变化伴随着促凋亡信号通路的激活。
Atrial fibrillation (AF) is characterized by irregular contractions of atrial cardiomyocytes and increased energy demand. The aim of this study was to characterize the influence of arrhythmia on glucose and fatty acid (FA) metabolism in cardiomyocytes, mice and human left atrial myocardium. Compared to regular pacing, irregular (pseudorandom variation at the same number of contractions/min) pacing of neonatal rat cardiomyocytes induced shorter action potential durations and effective refractory periods and increased diastolic [Ca2+](c). This was associated with the activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and AMP-activated protein kinase (AMPK). Membrane expression of fatty acid translocase (FAT/CD36) and C-14-palmitic acid uptake were augmented while membrane expression of glucose transporter subtype 4 (GLUT-4) as well as H-3-glucose uptake were reduced. Inhibition of AMPK and CaMKII prevented these arrhythmia-induced metabolic changes. Similar alterations of FA metabolism were observed in a transgenic mouse model (RacET) for spontaneousAF. Consistent with these findings samples of left atrial myocardium of patients with AF compared to matched samples of patients with sinus rhythm showed up-regulation of CaMKII and AMPK and increased membrane expression of FAT/CD36, resulting in lipid accumulation. These changes ofFAmetabolismwere accompanied by decreasedmembrane expression of GLUT-4, increased glycogen content and increased expression of the pro-apoptotic protein bax. Irregular pacing of cardiomyocytes increases diastolic [Ca2+](c) and activation of CaMKII and AMPK resulting in lipid accumulation, reduced glucose uptake and increased glycogen synthesis. These metabolic changes are accompanied by an activation of pro-apoptotic signalling pathways.