Objectives Beta 3-adrenoceptor (β3-AR) is closely associated with the energy metabolism. This study aimed to explore the role of β3-AR in energy remodelling in rabbit model of pacing-induced atrial fibrillation (AF).
Methods Rabbits with 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). Cardiac tissue and plasma were collected to evaluate the key regulator in glucose metabolism and fatty acid metabolism, glucose transporter-4 (GLUT-4) and carnitine-palmitoyl transferase I (CPT-1). The core regulator of the metabolism, peroxisome proliferator-activated receptor-α (PPAR-α) and PPAR co-activator (PGC-1α), were measured by RT-PCR and western blot (WB).
Results RT-PCR and WB results showed that β3-AR was significantly up-regulated in the pacing group in which high AF inducibility (6 out of 8, about 75%) and significantly decreased AERP200 (71.67 ± 5.77 vs. 95.00 ± 5.00 ms in control group, p < 0.01) were observed. Moreover, ATP concentration (15.33 ± 3.06 vs. 21.58 ± 0.52 μmol/gprot, p = 0.20) did have a decline trend although it didn’t reach the statistic difference. Inhibition of β3-AR decreased AF induction rate (37.5%), reversed AERP200 (77.67 ± 2.52 vs. 71.67 ± 5.77 ms in P7 group, p < 0.01) reduction, and restored ATP level in the AF rabbits. Further activation of β3-AR using agonist BRL37344 exacerbated AF-induced metabolic disruption. The periodic acid schiff (PAS) staining and Oil Red O staining showed β3-AR-dependent glycogen and lipid droplets accumulation in cardiac myocytes with AF. Inhibition of β3-AR also decreased the plasma fatty acid level but increased the tissue fatty acid level. Real- time PCR and WB results showed that GLUT-4 and CPT-1 were significantly down-regulated in the pacing group. Reduced glucose transportation and fatty acid oxidation could be restored by inhibition of β3-AR. Furthermore, key regulators of metabolism, PPAR-α and PGC-1α can be regulated by pharmacological intervention of the β3-AR, suggesting that PPARα/PGC-1α signalling pathway might be the down-stream molecular machinery in response to AF-induced activation of β3-AR.
Conclusions This study provided evidence for the regulating role of β3-AR in AF-induced metabolic remodeling. Pacing-induced AF causes activation of β3-AR and disrupted energy metabolism. Inhibition of β3-AR suppresses AF-caused metabolic disruption via regulating PPAR-α/PGC-1α pathway. This study suggest that β3-AR might be a potential novel target for AF therapy.