title: β3-Adrenoceptor Impairs Mitochondrial Biogenesis and Energy Metabolism During Rapid Atrial Pacing-Induced Atrial Fibrillation.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Jingmei
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Guangzhong
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Yixi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Ultrasonic Cardiogram Room, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Yang
authors.affiliation: Centre for Drug Safety Evaluation, Heilongjiang University of Chinese Medicine, Harbin, China.
authors.forename: Yongwu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Guanqi
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Jingpu
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Cardiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Cheping
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Cardiology, First Hospital of Harbin City, Harbin, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China liweimin_2009@163.com.
authors.forename: Weimin
authors.initials: W
authors.lastname: Li
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology; D058673:Adrenergic beta-3 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D016280:Atrial Function, Right; D064752:Atrial Remodeling; D002304:Cardiac Pacing, Artificial; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation; D006339:Heart Rate; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D051265:NF-E2-Related Factor 1 / Q000235:genetics / Q000378:metabolism; D001678:Organelle Biogenesis; D010725:Phosphocreatine / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000378:metabolism; D011817:Rabbits; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000227:Adenine Nucleotides; D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D000889:Anti-Arrhythmia Agents; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D051265:NF-E2-Related Factor 1; D022702:Receptors, Adrenergic, beta-3; D010725:Phosphocreatine; D003576:Electron Transport Complex IV; D006180:Proton-Translocating ATPases
keywords: atrial fibrillation; metabolic remodeling; mitochondrial biogenesis; β3-adrenoceptor