Dong Jingmei, Zhao Jingjing, Zhang Miaomiao, Liu Guangzhong, Wang Xiaobing, Liu Yixi, Yang Ning, Liu Yongwu, Zhao Guanqi, Sun Jiayu, Tian Jingpu, Cheng Cheping, Wei Lin, Li Yue, Li Weimin
Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
Ultrasonic Cardiogram Room, First Affiliated Hospital of Harbin Medical University, Harbin, China.
J Cardiovasc Pharmacol Ther. 2016 Jan;21(1):114-26. doi: 10.1177/1074248415590440. Epub 2015 Jun 30.
The β3-adrenoceptor (β3-AR) is implicated in cardiac remodeling. Since metabolic dysfunction due to loss of mitochondria plays an important role in heart diseases, we examined the effects of β3-AR on mitochondrial biogenesis and energy metabolism in atrial fibrillation (AF).
Atrial fibrillation was created by rapid atrial pacing in adult rabbits. Rabbits were randomly divided into 4 groups: control, pacing (P7), β3-AR antagonist (L748337), and β3-AR agonist (BRL37344) groups. Atrial effective refractory period (AERP) and AF induction rate were measured. Atrial concentrations of adenine nucleotides and phosphocreatine were quantified through high-performance liquid chromatography. Mitochondrial DNA content was determined. Real-time polymerase chain reaction and Western blot were used to examine the expression levels of signaling intermediates related to mitochondrial biogenesis.
After pacing for 7 days, β3-AR was significantly upregulated, AERP was reduced, and the AF induction rate was increased. The total adenine nucleotides pool was significantly reduced due to the decrease in adenosine triphosphate (ATP). The P7 group showed decreased activity of F0F1-ATPase. Mitochondrial DNA content was decreased and mitochondrial respiratory chain subunits were downregulated after pacing. Furthermore, expression of transcription factors involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (Tfam), was lower in the P7 group in response to β3-AR activation. Further stimulation of β3-AR with BRL37344 exacerbated these effects, together with a significant decrease in the levels of phosphocreatine. In contrast, inhibition of β3-AR with L748337 partially restored mitochondrial biogenesis and energy metabolism of atria in the paced rabbits.
The activation of β3-AR contributes to atrial metabolic remodeling via transcriptional downregulation of PGC-1α/NRF-1/Tfam pathway that are involved in mitochondrial biogenesis, which ultimately perturbs mitochondrial function in rapid pacing-induced AF. The β3-AR is therefore a potential novel therapeutic target for the treatment or prevention of AF.
β3-肾上腺素能受体（β3-AR）与心脏重塑有关。由于线粒体丢失导致的代谢功能障碍在心脏病中起重要作用，我们研究了β3-AR对心房颤动（AF）中线粒体生物发生和能量代谢的影响。
通过对成年兔快速心房起搏制造心房颤动。将兔随机分为4组：对照组、起搏组（P7）、β3-AR拮抗剂组（L748337）和β3-AR激动剂组（BRL37344）。测量心房有效不应期（AERP）和房颤诱发率。通过高效液相色谱法定量心房中腺嘌呤核苷酸和磷酸肌酸的浓度。测定线粒体DNA含量。采用实时聚合酶链反应和蛋白质免疫印迹法检测与线粒体生物发生相关的信号中间体的表达水平。
起搏7天后，β3-AR显著上调，AERP降低，房颤诱发率增加。由于三磷酸腺苷（ATP）减少，总腺嘌呤核苷酸池显著减少。P7组显示F0F1-ATP酶活性降低。起搏后线粒体DNA含量降低，线粒体呼吸链亚基下调。此外，响应β3-AR激活，P7组中参与线粒体生物发生的转录因子，包括过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）、核呼吸因子1（NRF-1）和线粒体转录因子A（Tfam）的表达较低。用BRL37344进一步刺激β3-AR加剧了这些影响，同时磷酸肌酸水平显著降低。相反，用L748337抑制β3-AR可部分恢复起搏兔心房的线粒体生物发生和能量代谢。
β3-AR的激活通过参与线粒体生物发生的PGC-1α/NRF-1/Tfam途径的转录下调导致心房代谢重塑，最终扰乱快速起搏诱导的房颤中的线粒体功能。因此，β3-AR是治疗或预防房颤潜在的新型治疗靶点。
