title: The PPAR pan-agonist bezafibrate ameliorates cardiomyopathy in a mouse model of Barth syndrome.
abstract: The PGC-1α/PPAR axis has been proposed as a potential therapeutic target for several metabolic disorders. The aim was to evaluate the efficacy of the pan-PPAR agonist, bezafibrate, in tafazzin knockdown mice (TazKD), a mouse model of Barth syndrome that exhibits age-dependent dilated cardiomyopathy with left ventricular (LV) dysfunction.
  
  
  
  The effect of bezafibrate on cardiac function was evaluated by echocardiography in TazKD mice with or without beta-adrenergic stress. Adrenergic stress by chronic isoproterenol infusion exacerbates the cardiac phenotype in TazKD mice, significantly depressing LV systolic function by 4.5 months of age. Bezafibrate intake over 2 months substantially ameliorates the development of LV systolic dysfunction in isoproterenol-stressed TazKD mice. Without beta-adrenergic stress, TazKD mice develop dilated cardiomyopathy by 7 months of age. Prolonged treatment with suprapharmacological dose of bezafibrate (0.5% in rodent diet) over a 4-month period effectively prevented LV dilation in mice isoproterenol treatment. Bezafibrate increased mitochondrial biogenesis, however also promoted oxidative stress in cardiomyocytes. Surprisingly, improvement of systolic function in bezafibrate-treated mice was accompanied with simultaneous reduction of cardiolipin content and increase of monolysocardiolipin levels in cardiac muscle.
  
  
  
  Thus, we demonstrate that bezafibrate has a potent therapeutic effect on preventing cardiac dysfunction in a mouse model of Barth syndrome with obvious implications for treating the human disease. Additional studies are needed to assess the potential benefits of PPAR agonists in humans with Barth syndrome.
authors.affiliation: The Heart Institute, Department of Pediatrics, the University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH, 45229-7020, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: The Heart Institute, Department of Pediatrics, the University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH, 45229-7020, USA.
authors.forename: Corey
authors.initials: C
authors.lastname: Powers
authors.affiliation: The Heart Institute, Department of Pediatrics, the University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH, 45229-7020, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Moore
authors.affiliation: The Heart Institute, Department of Pediatrics, the University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH, 45229-7020, USA.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Schafer
authors.affiliation: Departments of Anesthesiology and Cell Biology, New York University School of Medicine, New York, NY, USA.
authors.forename: Mindong
authors.initials: M
authors.lastname: Ren
authors.affiliation: Department of Pediatrics, New York University School of Medicine, New York, NY, USA.
authors.forename: Colin K L
authors.initials: CK
authors.lastname: Phoon
authors.affiliation: The Heart Institute, Department of Pediatrics, the University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH, 45229-7020, USA.
authors.forename: Jeanne F
authors.initials: JF
authors.lastname: James
authors.affiliation: Department of Biochemistry, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Glukhov
authors.affiliation: Department of Physiology, University of Puerto Rico School of Medicine, San Juan, Puerto Rico.
authors.forename: Sabzali
authors.initials: S
authors.lastname: Javadov
authors.affiliation: Academic Medical Center, Department of Clinical Chemistry and Pediatrics, Laboratory of Genetic Metabolic Disease (F0-224), Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Frédéric M
authors.initials: FM
authors.lastname: Vaz
authors.affiliation: The Heart Institute, Department of Pediatrics, the University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH, 45229-7020, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Jefferies
authors.affiliation: The Heart Institute, Department of Pediatrics, the University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH, 45229-7020, USA.
authors.forename: Arnold W
authors.initials: AW
authors.lastname: Strauss
authors.affiliation: The Heart Institute, Department of Pediatrics, the University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH, 45229-7020, USA. zaza.khuchua@cchmc.org.
authors.forename: Zaza
authors.identifier: 0000-0003-3582-5670
authors.initials: Z
authors.lastname: Khuchua
mesh_terms: D000818:Animals; D056889:Barth Syndrome / Q000188:drug therapy* / Q000378:metabolism; D001629:Bezafibrate / Q000627:therapeutic use*; D015153:Blotting, Western; D002308:Cardiolipins / Q000378:metabolism; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D008297:Male; D051379:Mice; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D016133:Polymerase Chain Reaction
chemical_list: D002308:Cardiolipins; D047492:Peroxisome Proliferator-Activated Receptors; D001629:Bezafibrate
keywords: Barth syndrome; Cardiolipin; Cardiomyopathy; Fibrates; Mitochondria; Systolic dysfunction