title: Fish oil constituent eicosapentaenoic acid inhibits endothelin-induced cardiomyocyte hypertrophy via PPAR-α.
abstract: OBJECTIVE
  A growing body of evidence shows the cardiovascular benefits of fish oil ingredients, including eicosapentaenoic acid (EPA), in humans and experimental animals. However, the effects of EPA on endothelin (ET)-1-induced cardiomyocyte hypertrophy and the involved signaling cascade are largely unknown. A previous study has demonstrated that peroxisomal proliferator-activated receptor (PPAR)-α ligand (fenofibrate) prevents ET-1-induced cardiomyocyte hypertrophy. Although EPA is a ligand of PPAR-α, to date, no study has examined a relationship between EPA and PPAR-α in cardiomyocyte hypertrophy. Here, we investigated whether EPA can block ET-1-induced cardiomyocyte hypertrophy and the possible underlying mechanisms.
  
  
  METHODS
  At day 4 of culture, neonatal rat cardiomyocytes were divided into four groups: control, control cells treated with EPA (10 μM), ET-1 (0.1 nM) administered only and EPA-pre-treated ET-1 administered groups. Also, the cardiomyocytes were treated with PPAR-α siRNA in order to elucidate the mechanisms that may underlie suppression of hypertrophy via the EPA-PPAR system.
  
  
  RESULTS
  Following ET-1 treatment, 2.12- and 1.92-fold increases in surface area and total protein synthesis rate in cardiomyocytes, respectively, were observed and these changes were greatly blocked by EPA pre-treatment. Further, the expression of PPAR-α increased in EPA-treated groups. PPAR-PPRE binding activity was suppressed in ET-1 administered cardiomyocyte and this suppression was improved by EPA treatment. Lastly, pre-treatment of cardiomyocytes with PPAR-α siRNA prior to EPA treatment attenuated the suppressing effects of EPA on cardiomyocyte hypertrophy.
  
  
  CONCLUSIONS
  In conclusion, the present study shows that EPA attenuates ET-1 induced cardiomyocyte hypertrophy by up regulating levels of PPAR-α pathway.
authors.affiliation: Department of Cardiovascular Medicine, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba; Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: nokeshimojo@yahoo.co.jp.
authors.forename: Nobutake
authors.initials: N
authors.lastname: Shimojo
authors.affiliation: Department of Cardiovascular Medicine, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba; Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: jsubrina@gmail.com.
authors.forename: Subrina
authors.initials: S
authors.lastname: Jesmin
authors.affiliation: Department of Cardiovascular Medicine, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba. Electronic address: ssakai@md.tsukuba.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sakai
authors.affiliation: Department of Cardiovascular Medicine, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba; Division of Sports Medicine, Faculty of Health and Sport Sciences, University of Tsukuba. Electronic address: maeda@taiiku.tsukuba.ac.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Maeda
authors.affiliation: Department of Cardiovascular Medicine, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba. Electronic address: t-miyauc@md.tsukuba.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyauchi
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: mizutani@md.tsukuba.ac.jp.
authors.forename: Taro
authors.initials: T
authors.lastname: Mizutani
authors.affiliation: Department of Cardiovascular Medicine, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba. Electronic address: kaonuma@md.tsukuba.ac.jp.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Aonuma
authors.affiliation: Department of Cardiovascular Medicine, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba; Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: kawano_s@md.tsukuba.ac.jp.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kawano
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006332:Cardiomegaly / Q000188:drug therapy*; D002457:Cell Extracts; D015118:Eicosapentaenoic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D016232:Endothelins; D005395:Fish Oils / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D015151:Immunoblotting; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology*; D047493:PPAR alpha / Q000378:metabolism*; D017207:Rats, Sprague-Dawley
chemical_list: D002457:Cell Extracts; D016232:Endothelins; D005395:Fish Oils; D047493:PPAR alpha; D015118:Eicosapentaenoic Acid
keywords: Cardiomyocyte; eicosapentaenoic acid; endothelin; hypertrophy; peroxisome proliferator-activated receptor - α