Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR‐α/sirtuin 1/PGC‐1α pathway
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. Th...
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| Veröffentlicht in: | British journal of pharmacology 2016-03, Vol.173 (6), p.1095-1109 |
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| creator | Liu, Guang‐zhong Hou, Ting‐ting Yuan, Yue Hang, Peng‐zhou Zhao, Jing‐jing Sun, Li Zhao, Guan‐qi Zhao, Jing Dong, Jing‐mei Wang, Xiao‐bing Shi, Hang Liu, Yong‐wu Zhou, Jing‐hua Dong, Zeng‐xiang Liu, Yang Zhan, Cheng‐chuang Li, Yue Li, Wei‐min |
| description | 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. |
| doi_str_mv | 10.1111/bph.13438 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5341245</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1770880473</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3918-ed43c0db5f79b43d790dc03f7334bb9e8c95acd28d5f04285b7735f28e0f71e33</originalsourceid><addsrcrecordid>eNqNkdFKHDEUhkNpqavthS9QBnpTL8ZNJskmc1PQpWpBcJH2OiSZzE4kM9kmGWXv-gh9FV_Eh-iTNNtVqULB3ARyvnycc34A9hE8RPlM1ao7RJhg_gpMEGGzkmKOXoMJhJCVCHG-A3ZjvIIwFxl9C3aqGeOMwtkEXJ-YwbdWBZlMYYfOKptiIVOw0hW9SVJ5Z3URTO8b45wdlpl6qG_-Wedksn4oUhf8uOyKxeLo8vfPX3e302hDGjONpovTeX5Cd7fFSqbuRq7fgTetdNG8v7_3wPeTL9_mZ-X5xenX-dF5qXGNeGkagjVsFG1ZrQhuWA0bDXHLMCZK1YbrmkrdVLyhLSQVp4oxTNuKG9gyZDDeA5-33tWoetNoM6QgnVgF28uwFl5a8bQy2E4s_bWgmKCK0Cz4dC8I_sdoYhK9jTpvQg7Gj1EgxiFFvKKzF6AMcg4J27T18Rl65ccw5E2ICmKKMSdoIzzYUjr4GINpH_tGUGyCFzl48Tf4zH74d9BH8iHpDEy3wI11Zv1_kzhenG2VfwCAc7vq</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2035338416</pqid></control><display><type>article</type><title>Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR‐α/sirtuin 1/PGC‐1α pathway</title><source>Wiley Free Content</source><source>Wiley Online Library - AutoHoldings Journals</source><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Liu, Guang‐zhong ; Hou, Ting‐ting ; Yuan, Yue ; Hang, Peng‐zhou ; Zhao, Jing‐jing ; Sun, Li ; Zhao, Guan‐qi ; Zhao, Jing ; Dong, Jing‐mei ; Wang, Xiao‐bing ; Shi, Hang ; Liu, Yong‐wu ; Zhou, Jing‐hua ; Dong, Zeng‐xiang ; Liu, Yang ; Zhan, Cheng‐chuang ; Li, Yue ; Li, Wei‐min</creator><creatorcontrib>Liu, Guang‐zhong ; Hou, Ting‐ting ; Yuan, Yue ; Hang, Peng‐zhou ; Zhao, Jing‐jing ; Sun, Li ; Zhao, Guan‐qi ; Zhao, Jing ; Dong, Jing‐mei ; Wang, Xiao‐bing ; Shi, Hang ; Liu, Yong‐wu ; Zhou, Jing‐hua ; Dong, Zeng‐xiang ; Liu, Yang ; Zhan, Cheng‐chuang ; Li, Yue ; Li, Wei‐min</creatorcontrib><description>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.</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1111/bph.13438</identifier><identifier>PMID: 26787506</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>Accumulation ; Adenine ; Animal models ; Animals ; Atria ; Atrial Fibrillation - drug therapy ; Atrial Fibrillation - metabolism ; Atrial Fibrillation - pathology ; Atrial Remodeling - drug effects ; Carbazoles - pharmacology ; Cardiac arrhythmia ; Cell culture ; Cell Line ; Droplets ; Electrophysiology ; Energy metabolism ; Fenofibrate ; Fenofibrate - pharmacology ; Fenofibrate - therapeutic use ; Fibrillation ; Glycogen ; Heart Atria - drug effects ; Heart Atria - metabolism ; Heart Atria - pathology ; Heart Atria - physiopathology ; Humans ; Male ; Metabolism ; Metabolites ; Middle Aged ; Nucleotides ; Oxazoles - pharmacology ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism ; Peroxisome proliferator-activated receptors ; PPAR alpha - agonists ; PPAR alpha - antagonists & inhibitors ; PPAR alpha - metabolism ; Proteins ; Rabbits ; Refractory period ; Research Paper ; Research Papers ; Sirtuin 1 - antagonists & inhibitors ; Sirtuin 1 - metabolism ; Tyrosine - analogs & derivatives ; Tyrosine - pharmacology</subject><ispartof>British journal of pharmacology, 2016-03, Vol.173 (6), p.1095-1109</ispartof><rights>2016 The British Pharmacological Society</rights><rights>2016 The British Pharmacological Society.</rights><rights>Copyright Blackwell Publishing Ltd. Mar 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3918-ed43c0db5f79b43d790dc03f7334bb9e8c95acd28d5f04285b7735f28e0f71e33</citedby><cites>FETCH-LOGICAL-c3918-ed43c0db5f79b43d790dc03f7334bb9e8c95acd28d5f04285b7735f28e0f71e33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341245/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341245/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,1411,1427,27901,27902,45550,45551,46384,46808,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26787506$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Guang‐zhong</creatorcontrib><creatorcontrib>Hou, Ting‐ting</creatorcontrib><creatorcontrib>Yuan, Yue</creatorcontrib><creatorcontrib>Hang, Peng‐zhou</creatorcontrib><creatorcontrib>Zhao, Jing‐jing</creatorcontrib><creatorcontrib>Sun, Li</creatorcontrib><creatorcontrib>Zhao, Guan‐qi</creatorcontrib><creatorcontrib>Zhao, Jing</creatorcontrib><creatorcontrib>Dong, Jing‐mei</creatorcontrib><creatorcontrib>Wang, Xiao‐bing</creatorcontrib><creatorcontrib>Shi, Hang</creatorcontrib><creatorcontrib>Liu, Yong‐wu</creatorcontrib><creatorcontrib>Zhou, Jing‐hua</creatorcontrib><creatorcontrib>Dong, Zeng‐xiang</creatorcontrib><creatorcontrib>Liu, Yang</creatorcontrib><creatorcontrib>Zhan, Cheng‐chuang</creatorcontrib><creatorcontrib>Li, Yue</creatorcontrib><creatorcontrib>Li, Wei‐min</creatorcontrib><title>Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR‐α/sirtuin 1/PGC‐1α pathway</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>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.</description><subject>Accumulation</subject><subject>Adenine</subject><subject>Animal models</subject><subject>Animals</subject><subject>Atria</subject><subject>Atrial Fibrillation - drug therapy</subject><subject>Atrial Fibrillation - metabolism</subject><subject>Atrial Fibrillation - pathology</subject><subject>Atrial Remodeling - drug effects</subject><subject>Carbazoles - pharmacology</subject><subject>Cardiac arrhythmia</subject><subject>Cell culture</subject><subject>Cell Line</subject><subject>Droplets</subject><subject>Electrophysiology</subject><subject>Energy metabolism</subject><subject>Fenofibrate</subject><subject>Fenofibrate - pharmacology</subject><subject>Fenofibrate - therapeutic use</subject><subject>Fibrillation</subject><subject>Glycogen</subject><subject>Heart Atria - drug effects</subject><subject>Heart Atria - metabolism</subject><subject>Heart Atria - pathology</subject><subject>Heart Atria - physiopathology</subject><subject>Humans</subject><subject>Male</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Middle Aged</subject><subject>Nucleotides</subject><subject>Oxazoles - pharmacology</subject><subject>Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism</subject><subject>Peroxisome proliferator-activated receptors</subject><subject>PPAR alpha - agonists</subject><subject>PPAR alpha - antagonists & inhibitors</subject><subject>PPAR alpha - metabolism</subject><subject>Proteins</subject><subject>Rabbits</subject><subject>Refractory period</subject><subject>Research Paper</subject><subject>Research Papers</subject><subject>Sirtuin 1 - antagonists & inhibitors</subject><subject>Sirtuin 1 - metabolism</subject><subject>Tyrosine - analogs & derivatives</subject><subject>Tyrosine - pharmacology</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkdFKHDEUhkNpqavthS9QBnpTL8ZNJskmc1PQpWpBcJH2OiSZzE4kM9kmGWXv-gh9FV_Eh-iTNNtVqULB3ARyvnycc34A9hE8RPlM1ao7RJhg_gpMEGGzkmKOXoMJhJCVCHG-A3ZjvIIwFxl9C3aqGeOMwtkEXJ-YwbdWBZlMYYfOKptiIVOw0hW9SVJ5Z3URTO8b45wdlpl6qG_-Wedksn4oUhf8uOyKxeLo8vfPX3e302hDGjONpovTeX5Cd7fFSqbuRq7fgTetdNG8v7_3wPeTL9_mZ-X5xenX-dF5qXGNeGkagjVsFG1ZrQhuWA0bDXHLMCZK1YbrmkrdVLyhLSQVp4oxTNuKG9gyZDDeA5-33tWoetNoM6QgnVgF28uwFl5a8bQy2E4s_bWgmKCK0Cz4dC8I_sdoYhK9jTpvQg7Gj1EgxiFFvKKzF6AMcg4J27T18Rl65ccw5E2ICmKKMSdoIzzYUjr4GINpH_tGUGyCFzl48Tf4zH74d9BH8iHpDEy3wI11Zv1_kzhenG2VfwCAc7vq</recordid><startdate>201603</startdate><enddate>201603</enddate><creator>Liu, Guang‐zhong</creator><creator>Hou, Ting‐ting</creator><creator>Yuan, Yue</creator><creator>Hang, Peng‐zhou</creator><creator>Zhao, Jing‐jing</creator><creator>Sun, Li</creator><creator>Zhao, Guan‐qi</creator><creator>Zhao, Jing</creator><creator>Dong, Jing‐mei</creator><creator>Wang, Xiao‐bing</creator><creator>Shi, Hang</creator><creator>Liu, Yong‐wu</creator><creator>Zhou, Jing‐hua</creator><creator>Dong, Zeng‐xiang</creator><creator>Liu, Yang</creator><creator>Zhan, Cheng‐chuang</creator><creator>Li, Yue</creator><creator>Li, Wei‐min</creator><general>Blackwell Publishing Ltd</general><general>John Wiley and Sons Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TK</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>7U7</scope><scope>C1K</scope><scope>5PM</scope></search><sort><creationdate>201603</creationdate><title>Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR‐α/sirtuin 1/PGC‐1α pathway</title><author>Liu, Guang‐zhong ; Hou, Ting‐ting ; Yuan, Yue ; Hang, Peng‐zhou ; Zhao, Jing‐jing ; Sun, Li ; Zhao, Guan‐qi ; Zhao, Jing ; Dong, Jing‐mei ; Wang, Xiao‐bing ; Shi, Hang ; Liu, Yong‐wu ; Zhou, Jing‐hua ; Dong, Zeng‐xiang ; Liu, Yang ; Zhan, Cheng‐chuang ; Li, Yue ; Li, Wei‐min</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3918-ed43c0db5f79b43d790dc03f7334bb9e8c95acd28d5f04285b7735f28e0f71e33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Accumulation</topic><topic>Adenine</topic><topic>Animal models</topic><topic>Animals</topic><topic>Atria</topic><topic>Atrial Fibrillation - drug therapy</topic><topic>Atrial Fibrillation - metabolism</topic><topic>Atrial Fibrillation - pathology</topic><topic>Atrial Remodeling - drug effects</topic><topic>Carbazoles - pharmacology</topic><topic>Cardiac arrhythmia</topic><topic>Cell culture</topic><topic>Cell Line</topic><topic>Droplets</topic><topic>Electrophysiology</topic><topic>Energy metabolism</topic><topic>Fenofibrate</topic><topic>Fenofibrate - pharmacology</topic><topic>Fenofibrate - therapeutic use</topic><topic>Fibrillation</topic><topic>Glycogen</topic><topic>Heart Atria - drug effects</topic><topic>Heart Atria - metabolism</topic><topic>Heart Atria - pathology</topic><topic>Heart Atria - physiopathology</topic><topic>Humans</topic><topic>Male</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Middle Aged</topic><topic>Nucleotides</topic><topic>Oxazoles - pharmacology</topic><topic>Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism</topic><topic>Peroxisome proliferator-activated receptors</topic><topic>PPAR alpha - agonists</topic><topic>PPAR alpha - antagonists & inhibitors</topic><topic>PPAR alpha - metabolism</topic><topic>Proteins</topic><topic>Rabbits</topic><topic>Refractory period</topic><topic>Research Paper</topic><topic>Research Papers</topic><topic>Sirtuin 1 - antagonists & inhibitors</topic><topic>Sirtuin 1 - metabolism</topic><topic>Tyrosine - analogs & derivatives</topic><topic>Tyrosine - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Guang‐zhong</creatorcontrib><creatorcontrib>Hou, Ting‐ting</creatorcontrib><creatorcontrib>Yuan, Yue</creatorcontrib><creatorcontrib>Hang, Peng‐zhou</creatorcontrib><creatorcontrib>Zhao, Jing‐jing</creatorcontrib><creatorcontrib>Sun, Li</creatorcontrib><creatorcontrib>Zhao, Guan‐qi</creatorcontrib><creatorcontrib>Zhao, Jing</creatorcontrib><creatorcontrib>Dong, Jing‐mei</creatorcontrib><creatorcontrib>Wang, Xiao‐bing</creatorcontrib><creatorcontrib>Shi, Hang</creatorcontrib><creatorcontrib>Liu, Yong‐wu</creatorcontrib><creatorcontrib>Zhou, Jing‐hua</creatorcontrib><creatorcontrib>Dong, Zeng‐xiang</creatorcontrib><creatorcontrib>Liu, Yang</creatorcontrib><creatorcontrib>Zhan, Cheng‐chuang</creatorcontrib><creatorcontrib>Li, Yue</creatorcontrib><creatorcontrib>Li, Wei‐min</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Guang‐zhong</au><au>Hou, Ting‐ting</au><au>Yuan, Yue</au><au>Hang, Peng‐zhou</au><au>Zhao, Jing‐jing</au><au>Sun, Li</au><au>Zhao, Guan‐qi</au><au>Zhao, Jing</au><au>Dong, Jing‐mei</au><au>Wang, Xiao‐bing</au><au>Shi, Hang</au><au>Liu, Yong‐wu</au><au>Zhou, Jing‐hua</au><au>Dong, Zeng‐xiang</au><au>Liu, Yang</au><au>Zhan, Cheng‐chuang</au><au>Li, Yue</au><au>Li, Wei‐min</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR‐α/sirtuin 1/PGC‐1α pathway</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>2016-03</date><risdate>2016</risdate><volume>173</volume><issue>6</issue><spage>1095</spage><epage>1109</epage><pages>1095-1109</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><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.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>26787506</pmid><doi>10.1111/bph.13438</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| source | Wiley Free Content; Wiley Online Library - AutoHoldings Journals; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Accumulation Adenine Animal models Animals Atria Atrial Fibrillation - drug therapy Atrial Fibrillation - metabolism Atrial Fibrillation - pathology Atrial Remodeling - drug effects Carbazoles - pharmacology Cardiac arrhythmia Cell culture Cell Line Droplets Electrophysiology Energy metabolism Fenofibrate Fenofibrate - pharmacology Fenofibrate - therapeutic use Fibrillation Glycogen Heart Atria - drug effects Heart Atria - metabolism Heart Atria - pathology Heart Atria - physiopathology Humans Male Metabolism Metabolites Middle Aged Nucleotides Oxazoles - pharmacology Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism Peroxisome proliferator-activated receptors PPAR alpha - agonists PPAR alpha - antagonists & inhibitors PPAR alpha - metabolism Proteins Rabbits Refractory period Research Paper Research Papers Sirtuin 1 - antagonists & inhibitors Sirtuin 1 - metabolism Tyrosine - analogs & derivatives Tyrosine - pharmacology |
| title | Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR‐α/sirtuin 1/PGC‐1α pathway |
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