Guang-Zhong Liu1, Ting-Ting Hou1, Yue Yuan1, Peng-Zhou Hang2, Jing-Jing Zhao1, Li Sun1, Guan-Qi Zhao1, Jing Zhao3, Jing-Mei Dong1, Xiao-Bing Wang1, Hang Shi1, Yong-Wu Liu4, Jing-Hua Zhou5, Zeng-Xiang Dong3, Yang Liu1, Cheng-Chuang Zhan1, Yue Li1,3, Wei-Min Li1,3. 1. Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China. 2. Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China. 3. Key Laboratory of Cardiac Diseases and Heart, Failure of Harbin Medical University, Harbin, Heilongjiang Province, China. 4. Centre for Drug Safety Evaluation, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China. 5. Department of Morphology, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China.
Abstract
BACKGROUND AND PURPOSE: Atrial metabolic remodelling is critical for the process of atrial fibrillation (AF). The PPAR-α/sirtuin 1 /PPAR co-activator α (PGC-1α) pathway plays an important role in maintaining energy metabolism. However, the effect of the PPAR-α agonist fenofibrate on AF is unclear. Therefore, the aim of this study was to determine the effect of fenofibrate on atrial metabolic remodelling in AF and explore its possible mechanisms of action. EXPERIMENTAL APPROACH: The expression of metabolic proteins was examined in the left atria of AF patients. Thirty-two rabbits were divided into sham, AF (pacing with 600 beats·min(-1) for 1 week), fenofibrate treated (pretreated with fenofibrate before pacing) and fenofibrate alone treated (for 2 weeks) groups. HL-1 cells were subjected to rapid pacing in the presence or absence of fenofibrate, the PPAR-α antagonist GW6471 or sirtuin 1-specific inhibitor EX527. Metabolic factors, circulating biochemical metabolites, atrial electrophysiology, adenine nucleotide levels and accumulation of glycogen and lipid droplets were assessed. KEY RESULTS: The PPAR-α/sirtuin 1/PGC-1α pathway was significantly inhibited in AF patients and in the rabbit/HL-1 cell models, resulting in a reduction of key downstream metabolic factors; this effect was significantly restored by fenofibrate. Fenofibrate prevented the alterations in circulating biochemical metabolites, reduced the level of adenine nucleotides and accumulation of glycogen and lipid droplets, reversed the shortened atrial effective refractory period and increased risk of AF. CONCLUSION AND IMPLICATIONS: Fenofibrate inhibited atrial metabolic remodelling in AF by regulating the PPAR-α/sirtuin 1/PGC-1α pathway. The present study may provide a novel therapeutic strategy for AF.
BACKGROUND AND PURPOSE:Atrial metabolic remodelling is critical for the process of atrial fibrillation (AF). The PPAR-α/sirtuin 1 /PPAR co-activator α (PGC-1α) pathway plays an important role in maintaining energy metabolism. However, the effect of the PPAR-α agonist fenofibrate on AF is unclear. Therefore, the aim of this study was to determine the effect of fenofibrate on atrial metabolic remodelling in AF and explore its possible mechanisms of action. EXPERIMENTAL APPROACH: The expression of metabolic proteins was examined in the left atria of AFpatients. Thirty-two rabbits were divided into sham, AF (pacing with 600 beats·min(-1) for 1 week), fenofibrate treated (pretreated with fenofibrate before pacing) and fenofibrate alone treated (for 2 weeks) groups. HL-1 cells were subjected to rapid pacing in the presence or absence of fenofibrate, the PPAR-α antagonist GW6471 or sirtuin 1-specific inhibitor EX527. Metabolic factors, circulating biochemical metabolites, atrial electrophysiology, adenine nucleotide levels and accumulation of glycogen and lipid droplets were assessed. KEY RESULTS: The PPAR-α/sirtuin 1/PGC-1α pathway was significantly inhibited in AFpatients and in the rabbit/HL-1 cell models, resulting in a reduction of key downstream metabolic factors; this effect was significantly restored by fenofibrate. Fenofibrate prevented the alterations in circulating biochemical metabolites, reduced the level of adenine nucleotides and accumulation of glycogen and lipid droplets, reversed the shortened atrial effective refractory period and increased risk of AF. CONCLUSION AND IMPLICATIONS: Fenofibrate inhibited atrial metabolic remodelling in AF by regulating the PPAR-α/sirtuin 1/PGC-1α pathway. The present study may provide a novel therapeutic strategy for AF.
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Authors: Dimitrios A Vrachatis; Konstantinos A Papathanasiou; Konstantinos E Iliodromitis; Sotiria G Giotaki; Charalampos Kossyvakis; Konstantinos Raisakis; Andreas Kaoukis; Vaia Lambadiari; Dimitrios Avramides; Bernhard Reimers; Giulio G Stefanini; Michael Cleman; Georgios Giannopoulos; Alexandra Lansky; Spyridon G Deftereos Journal: Drugs Date: 2021-07-23 Impact factor: 9.546