title: Carbon monoxide improves cardiac function and mitochondrial population quality in a mouse model of metabolic syndrome.
abstract: OBJECTIVE
  Metabolic syndrome induces cardiac dysfunction associated with mitochondria abnormalities. As low levels of carbon monoxide (CO) may improve myocardial and mitochondrial activities, we tested whether a CO-releasing molecule (CORM-3) reverses metabolic syndrome-induced cardiac alteration through changes in mitochondrial biogenesis, dynamics and autophagy.
  
  
  RESULTS
  Mice were fed with normal diet (ND) or high-fat diet (HFD) for twelve weeks. Then, mice received two intraperitoneal injections of CORM-3 (10 mg x kg(-1)), with the second one given 16 hours after the first. Contractile function in isolated hearts and mitochondrial parameters were evaluated 24 hours after the last injection. Mitochondrial population was explored by electron microscopy. Changes in mitochondrial dynamics, biogenesis and autophagy were assessed by western-blot and RT-qPCR. Left ventricular developed pressure was reduced in HFD hearts. Mitochondria from HFD hearts presented reduced membrane potential and diminished ADP-coupled respiration. CORM-3 restored both cardiac and mitochondrial functions. Size and number of mitochondria increased in the HFD hearts but not in the CORM-3-treated HFD group. CORM-3 modulated HFD-activated mitochondrial fusion and biogenesis signalling. While autophagy was not activated in the HFD group, CORM-3 increased the autophagy marker LC3-II. Finally, ex vivo experiments demonstrated that autophagy inhibition by 3-methyladenine abolished the cardioprotective effects of CORM-3.
  
  
  CONCLUSIONS
  CORM-3 may modulate pathways controlling mitochondrial quality, thus leading to improvements of mitochondrial efficiency and HFD-induced cardiac dysfunction.
authors.affiliation: EA4484, Physiology Department, Lille 2 University, Lille, France. steve.lancel@univ-lille2.fr
authors.forename: Steve
authors.initials: S
authors.lastname: Lancel
authors.forename: David
authors.initials: D
authors.lastname: Montaigne
authors.forename: Xavier
authors.initials: X
authors.lastname: Marechal
authors.forename: Camille
authors.initials: C
authors.lastname: Marciniak
authors.forename: Sidi Mohamed
authors.initials: SM
authors.lastname: Hassoun
authors.forename: Brigitte
authors.initials: B
authors.lastname: Decoster
authors.forename: Caroline
authors.initials: C
authors.lastname: Ballot
authors.forename: Caroline
authors.initials: C
authors.lastname: Blazejewski
authors.forename: Delphine
authors.initials: D
authors.lastname: Corseaux
authors.forename: Bernadette
authors.initials: B
authors.lastname: Lescure
authors.forename: Roberto
authors.initials: R
authors.lastname: Motterlini
authors.forename: Remi
authors.initials: R
authors.lastname: Neviere
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D002248:Carbon Monoxide / Q000494:pharmacology*; D004041:Dietary Fats / Q000009:adverse effects; D005260:Female; D006331:Heart Diseases / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D024821:Metabolic Syndrome / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects*; D009942:Organometallic Compounds / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000963:Antimetabolites; D004041:Dietary Fats; D009942:Organometallic Compounds; C476530:tricarbonylchloro(glycinato)ruthenium(II); D002248:Carbon Monoxide