Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology · 2013
β3-adrenoceptor mediates metabolic protein remodeling in a rabbit model of tachypacing-induced atrial fibrillation.
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Liu Yixi, Geng Jianqiang, Liu Yutan, Li Yue, Shen Jingxia, Xiao Xingping, Sheng Li, Yang Baofeng, Cheng Cheping, Li Weimin
Аннотация
BACKGROUND: 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).
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
Предметные рубрики MeSH
Adenosine TriphosphateAdrenergic beta-3 Receptor AgonistsAdrenergic beta-3 Receptor AntagonistsAnimalsAtrial FibrillationCD36 AntigensCardiac Pacing, ArtificialDisease Models, AnimalDown-RegulationElectrocardiographyFatty AcidsGlucose Transporter Type 4Myocytes, CardiacPPAR alphaPropanolaminesRabbitsReceptors, Adrenergic, beta-3Signal TransductionTranscription FactorsUp-Regulation