title: Macrophage migration inhibitory factor induces contractile and mitochondria dysfunction by altering cytoskeleton network in the human heart.
abstract: OBJECTIVE
  Macrophage migration inhibitory factor (MIF) has been recognized as a potent proinflammatory mediator that may induce myocardial dysfunction. Mechanisms by which MIF affects cardiac function are not completely elucidated; yet, some macrophage migration inhibitory effects have been related to changes in cytoskeleton architecture. We hypothesized that MIF-induced myocardial dysfunction and mitochondrial respiration deficit could be related to cardiac cell microtubule dynamics alterations.
  
  
  METHODS
  Prospective, randomized study.
  
  
  METHODS
  Experimental Cardiovascular Laboratory, University Hospital.
  
  
  METHODS
  Human myocardial (atrial) trabeculae.
  
  
  METHODS
  Atrial trabeculae were obtained at the time of cardiac surgery. Isometrically contracting isolated human right atrial trabeculae were exposed to MIF (100 ng/mL) for 60 minutes, in the presence or not of pretreatment with colchicine (10 µM), a microtubule-depolymerizing agent, or paclitaxel (10 µM) a microtubule-stabilizing agent.
  
  
  RESULTS
  Maximal active isometric tension curve and developed isometric force were studied. Trabeculae were then permeabilized for mitochondrial respiration studies using high-resolution oxygraphy. Heart fiber electron microscopy and visualization of βIV tubulin and polymerized actin by confocal microscopy were used to evaluate sarcomere and microtubule disarray. Compared with controls, MIF elicited cardiac contractile and mitochondrial dysfunction, which were largely prevented by pretreatment with colchicine, but not by paclitaxel. Pretreatment with colchicine prevented MIF-induced microtubule network disorganization, excessive tubulin polymerization, and mitochondrial fragmentation. Compound-C, an inhibitor of AMP-activated protein kinase (AMPK), partially prevented contractile dysfunction, suggesting that cardiac deleterious effects of MIF were related to AMPK activation.
  
  
  CONCLUSIONS
  MIF depresses human myocardial contractile function and impairs mitochondrial respiration. Changes in microtubule network likely promote MIF-induced cardiac dysfunction by 1) altering with mitochondrial tubular assembly and outer membrane permeability for adenine nucleotides leading to energy deficit, 2) excessive tubulin polymerization that may impede cardiomyocyte viscosity and motion, and 3) interfering with AMPK pathway.
authors.affiliation: Departement de Physiologie (EA 4484), Faculte de Medecine, Universite Lille, IFR 114 (IMPRT), Lille, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Preau
authors.forename: David
authors.initials: D
authors.lastname: Montaigne
authors.forename: Thomas
authors.initials: T
authors.lastname: Modine
authors.forename: George
authors.initials: G
authors.lastname: Fayad
authors.forename: Mohamed
authors.initials: M
authors.lastname: Koussa
authors.forename: Meryem
authors.initials: M
authors.lastname: Tardivel
authors.forename: Alain
authors.initials: A
authors.lastname: Durocher
authors.forename: Fabienne
authors.initials: F
authors.lastname: Saulnier
authors.forename: Xavier
authors.initials: X
authors.lastname: Marechal
authors.forename: Remi
authors.initials: R
authors.lastname: Neviere
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors; D003078:Colchicine / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D009119:Muscle Contraction; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D019210:Troponin I / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D009566:Nitrates; D009573:Nitrites; D011720:Pyrazoles; D011743:Pyrimidines; D019210:Troponin I; D050257:Tubulin Modulators; D014409:Tumor Necrosis Factor-alpha; C516138:dorsomorphin; D019344:Lactic Acid; D055372:AMP-Activated Protein Kinases; D017239:Paclitaxel; D003078:Colchicine