Regulating the Warburg effect on metabolic stress and myocardial fibrosis remodeling and atrial intracardiac waveform activity induced by atrial fibrillation
Regulating the Warburg effect on metabolic stress and myocardial fibrosis remodeling and atrial intracardiac waveform activity induced by atrial fibrillation
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调节Warburg效应对心房颤动所致代谢应激及心肌纤维化重塑及心房心内波形活动的影响
DOI：
10.1016/j.bbrc.2019.06.055
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发表时间：
2019-08-27
影响因子：
3.1
通讯作者：
Jiang, Zhi-Sheng
中科院分区：
文献类型：
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作者：
Hu, Heng-Jing;Zhang, Chi;Jiang, Zhi-Sheng
心房颤动（AF）与代谢应激相关，并通过增加糖酵解诱导心肌纤维化重建。阵发性房颤（p-AF）治疗的目标之一是改善心肌纤维化重建和Warburg效应引起的心肌代谢应激。采用雄性犬快速右心房起搏（RAP）6天建立p-AF模型。在暴露于 p-AF 或非 p-AF 之前，用去氧肾上腺素 (PE) 或二氯乙酸 (DCA) 对犬科动物进行预处理。测量犬心房心肌细胞的 P 波持续时间 (P-max)、最小 P 波持续时间 (P-min)、P 波离散度 (PWD)、心房有效不应期 (AERP) 和 AERP 离散度 (AERPd)。通过蛋白质印迹和逆转录聚合酶链评估丙酮酸脱氢酶激酶-1 (PDK-1)、PDK-4、乳酸脱氢酶 A (LDHA)、丙酮酸脱氢酶 (PDH)、柠檬酸合酶 (CS)、异柠檬酸脱氢酶 (IDH) 和基质金属蛋白酶 9 (MMP-9) RTPCR法检测单磷酸腺苷（AMP）、三磷酸腺苷（ATP）、乳酸、糖原含量，酶联免疫吸附试验（ELISA）检测LDHA、PDK-1、PDK-4活性，PAS法检测心肌组织糖原含量，测定心肌纤维化重塑情况。 通过苏木精和伊红 (H&E) 以及 Masson 染色进行评估。我们的研究结果表明，p-AF 通过增加 PDK-1、PDK-4 和 LDHA 的表达和活性、AMP 和乳酸的含量以及 AMP/ATP 的比率，并降低 PDH、CS 和 IDH 的表达以及糖原含量来增加 Warburg 效应相关的代谢应激和心肌纤维化重塑。此外，p-AF可诱导心肌细胞纤维化重塑并增加MMP-9的表达，并且p-AF还通过延长P-max、P-min、PWD和AERPd以及缩短AERP来增加心房心内波形活动。 PDK亚型激动剂（PE）产生类似p-AF的病理效应，并能与p-AF产生协同效应，进一步增加Warburg效应相关的代谢应激、心肌纤维化重塑和心房心内波形活动。相比之下，使用 PDK 特异性抑制剂 (DCA) 可以完全逆转 p-AF 引起的这些病理生理变化。我们证明p-AF可以诱导犬心房心肌细胞的Warburg效应，并通过抑制Warburg效应显着改善p-AF诱导的代谢应激、心肌纤维化重塑和心房心内波形活动。 (C) 2019 Elsevier Inc. 保留所有权利。
Atrial fibrillation (AF) is associated with metabolic stress and induces myocardial fibrosis reconstruction by increasing glycolysis. One goal in the treatment of paroxysmal AF (p-AF) is to improve myocardial fibrosis reconstruction and myocardial metabolic stress caused by the Warburg effect. Adopted male canine that rapid right atrial pacing (RAP) for 6 days to establish a p-AF model. The canines were pre-treated with phenylephrine (PE) or dichloroacetic acid (DCA) before exposure to p-AF or non-p-AF. P-wave duration (P-max), minimum P-wave duration (P-min), P wave dispersion (PWD), atrial effective refractory period (AERP) and AERP dispersion (AERPd) were measured in canine atrial cardiomyocytes. Pyruvate dehydrogenase kinase-1 (PDK-1), PDK-4, lactate dehydrogenase A (LDHA), pyruvate dehydrogenase (PDH), citrate synthase (CS), isocitrate dehydrogenase (IDH), and matrix metalloproteinase 9 (MMP-9) were evaluated by western blotting and reverse transcription polymerase chain reaction (RTPCR), content of adenosine monophosphate (AMP), adenosine triphosphate (ATP), lactic acid and glycogen, and activity of LDHA, PDK-1 and PDK-4 were evaluated by enzyme-linked immunosorbent assay (ELISA), myocardial tissue glycogen content was evaluated by PAS, myocardial fibrosis remodeling was evaluated by hematoxylin and eosin (H&E) and Masson staining. Our findings demonstrated that p-AF increases the Warburg effect-related metabolic stress and myocardial fibrosis remodeling by increasing the expression and activity of PDK-1, PDK-4, and LDHA, content of AMP and lactic acid, and the ratio of AMP/ATP and decreasing the expression of PDH, CS, and IDH, and glycogen content. In addition, p-AF can induce cardiomyocyte fibrosis remodeling and increase MMP-9 expression, and p-AF also increases atrial intracardiac waveform activity by prolonging P-max, P-min, PWD, and AERPd and shortening AERP. PDK isoforms agonists (PE) produce a similar p-AF pathological effect and can produce synergistic effects with p-AF, further increasing Warburg effect-related metabolic stress, myocardial fibrosis remodeling, and atrial intracardiac waveform activity. In contrast, the use of PDK-specific inhibitors (DCA) completely reverses these pathophysiological changes induced by p-AF. We demonstrate that p-AF can induce the Warburg effect in canine atrial cardiomyocytes and significantly improve p-AF-induced metabolic stress, myocardial fibrosis remodeling, and atrial intracardiac waveform activity by inhibiting the Warburg effect. (C) 2019 Elsevier Inc. All rights reserved.