title: Eicosapentaenoic acid ameliorates palmitate-induced lipotoxicity via the AMP kinase/dynamin-related protein-1 signaling pathway in differentiated H9c2 myocytes.
abstract: Emerging evidence suggested the preferable effects of eicosapentaenoic acid (EPA; n-3 polyunsaturated fatty acid) against cardiac lipotoxicity, which worsens cardiac function by means of excessive serum free fatty acids due to chronic adrenergic stimulation under heart failure. Nonetheless, the precise molecular mechanisms remain elusive. In this study, we focused on dynamin-related protein-1 (Drp1) as a possible modulator of the EPA-mediated cardiac protection against cardiac lipotoxicity, and investigated the causal relation between AMP-activated protein kinase (AMPK) and Drp1.
  
  
  
  When differentiated H9c2 myocytes were exposed to palmitate (PAL; saturated fatty acid, 400µM) for 24h, these myocytes showed activation of caspases 3 and 7, enhanced caspase 3 cleavage, depolarized mitochondrial membrane potential, depleted intracellular ATP, and enhanced production of intracellular reactive oxygen species. These changes suggested lipotoxicity due to excessive PAL. PAL enhanced mitochondrial fragmentation with increased Drp1 expression, as well. EPA (50µM) restored the PAL-induced apoptosis, mitochondrial dysfunction, and mitochondrial fragmentation with increased Drp1 expression by PAL. EPA activated phosphorylation of AMPK, and pharmacological activation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleotide ameliorated the PAL-induced apoptosis, mitochondrial dysfunction, and downregulated Drp1. An AMPK knockdown via RNA interference enhanced Drp1 expression and attenuated the protective effects of EPA against the PAL-induced lipotoxicity.
  
  
  
  EPA ameliorates the PAL-induced lipotoxicity via AMPK activation, which subsequently suppresses mitochondrial fragmentation and Drp1 expression. Our findings may provide new insights into the molecular mechanisms of EPA-mediated myocardial protection in heart failure.
authors.affiliation: Division of Cardiology, Internal Medicine 3, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sakamoto
authors.affiliation: Division of Cardiology, Internal Medicine 3, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan. Electronic address: msaotome@hama-med.ac.jp.
authors.forename: Masao
authors.initials: M
authors.lastname: Saotome
authors.affiliation: Division of Cardiology, Internal Medicine 3, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
authors.forename: Prottoy
authors.initials: P
authors.lastname: Hasan
authors.affiliation: Division of Cardiology, Internal Medicine 3, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
authors.forename: Terumori
authors.initials: T
authors.lastname: Satoh
authors.affiliation: Division of Cardiology, Internal Medicine 3, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Ohtani
authors.affiliation: Division of Cardiology, Internal Medicine 3, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Urushida
authors.affiliation: Division of Cardiology, Internal Medicine 3, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Katoh
authors.affiliation: Division of Cardiology, Internal Medicine 3, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Satoh
authors.affiliation: Division of Cardiology, Internal Medicine 3, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
authors.forename: Hideharu
authors.initials: H
authors.lastname: Hayashi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002460:Cell Line; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D032386:Myoblasts, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010168:Palmitates / Q000633:toxicity; D051381:Rats; D015398:Signal Transduction
chemical_list: D002316:Cardiotonic Agents; D010168:Palmitates; D015118:Eicosapentaenoic Acid; D055372:AMP-Activated Protein Kinases; C519851:Dnm1l protein, rat; D034281:Dynamins
keywords: AMP kinase; Apoptosis; Dynamin-related protein-1; Eicosapentaenoic acid; Mitochondrial fragmentation; Palmitate