Liu Yixi, Geng Jianqiang, Liu Yutan, Li Yue, Shen Jingxia, Xiao Xingping, Sheng Li, Yang Baofeng, Cheng Cheping, Li Weimin
Department of Cardiology, The First Affiliated Hospital, Harbin Medical University, Harbin, China.
Cell Physiol Biochem. 2013;32(6):1631-42. doi: 10.1159/000356599. Epub 2013 Dec 5.
The beta 3-adrenoceptor (β3-AR) is closely associated with energy metabolism. This study aimed to explore the role of β3-AR in energy remodeling in a rabbit model of pacing-induced atrial fibrillation (AF).
Rabbits with a sham-operation or pacing-induced AF were used for this study, and the latter group was further divided into three subgroups: 1) the pacing group, 2) the β3-AR agonist (BRL37344)-treated group, and 3) the β3-AR antagonist (SR59230A)-treated group. Atrial electrogram morphology and surface ECG were used to monitor the induction of AF and atrial effective refractory period (AERP). RT-PCR and western blot (WB) were used to show alterations in β3-AR and metabolic-related protein.
RT-PCR and WB results showed that β3-AR was significantly upregulated in the pacing group, and that it corresponded with high AF inducibility and significantly decreased AERP200 and ATP production in this group. Inhibition of β3-AR decreased the AF induction rate, reversed AERP200 reduction, and restored ATP levels in the AF rabbits. Further activation of β3-AR using agonist BRL37344 exacerbated AF-induced metabolic disruption. Periodic acid Schiff (PAS) and Oil Red O staining showed β3-AR-dependent glycogen and lipid droplet accumulation in cardiac myocytes with AF. Glucose transporter-4 (GLUT-4) and CD36, key transporters of glucose and fatty acids, were downregulated in the pacing group. Expression of carnitine-palmitoyltransferase I (CPT-1), a key regulator in fatty acid metabolism, was also significantly downregulated in the pacing group. Reduced glucose transportation and fatty acid oxidation could be restored by inhibition of β3-AR. Furthermore, key regulators of metabolism, peroxisome proliferator-activated receptor-α (PPARα) and PPAR co-activator (PGC-1α) can be regulated by pharmacological intervention of the β3-AR.
β3-AR is involved in metabolic protein remodeling in AF. PPARα/PGC-1α signaling pathway might be the relevant down-stream molecular machinery in response to AF-induced activation of β3-AR. β3-AR might be a novel target in AF treatment.
β3-肾上腺素能受体（β3-AR）与能量代谢密切相关。本研究旨在探讨β3-AR在起搏诱导的心房颤动（AF）兔模型能量重塑中的作用。
本研究使用假手术或起搏诱导AF的兔子，后者进一步分为三个亚组：1）起搏组，2）β3-AR激动剂（BRL37344）治疗组，3）β3-AR拮抗剂（SR59230A）治疗组。利用心房电图形态和体表心电图监测AF的诱发及心房有效不应期（AERP）。采用逆转录-聚合酶链反应（RT-PCR）和蛋白质免疫印迹法（WB）检测β3-AR及代谢相关蛋白的变化。
RT-PCR和WB结果显示，起搏组β3-AR显著上调，且与该组高AF诱发率及显著降低的AERP200和ATP生成相对应。抑制β3-AR可降低AF兔的AF诱发率，逆转AERP200降低，并恢复ATP水平。使用激动剂BRL37344进一步激活β3-AR会加剧AF诱导的代谢紊乱。过碘酸希夫（PAS）染色和油红O染色显示，AF心肌细胞中糖原和脂滴积累依赖于β3-AR。葡萄糖转运蛋白4（GLUT-4）和脂肪酸转运关键蛋白CD36在起搏组中表达下调。脂肪酸代谢关键调节因子肉碱-棕榈酰转移酶I（CPT-1）在起搏组中的表达也显著下调。抑制β3-AR可恢复葡萄糖转运减少和脂肪酸氧化减少的情况。此外，通过β3-AR的药物干预可调节代谢关键调节因子过氧化物酶体增殖物激活受体-α（PPARα）和PPAR共激活因子（PGC-1α）。
β3-AR参与AF中的代谢蛋白重塑。PPARα/PGC-1α信号通路可能是响应AF诱导的β3-AR激活的相关下游分子机制。β3-AR可能是AF治疗的新靶点。
