title: Subendocardial increase in reactive oxygen species production affects regional contractile function in ischemic heart failure.
abstract: OBJECTIVE
  Heart failure (HF) is characterized by regionalized contractile alterations resulting in loss of the transmural contractile gradient across the left ventricular free wall. We tested whether a regional alteration in mitochondrial oxidative metabolism during HF could affect myofilament function through protein kinase A (PKA) signaling.
  
  
  RESULTS
  Twelve weeks after permanent left coronary artery ligation that induced myocardial infarction (MI), subendocardial (Endo) cardiomyocytes had decreased activity of complex I and IV of the mitochondrial electron transport chain and produced twice more superoxide anions than sham Endo and subepicardial cells. This effect was associated with a reduced antioxidant activity of superoxide dismutase and Catalase only in MI Endo cells. The myofilament contractile properties (Ca(2+) sensitivity and maximal tension), evaluated in skinned cardiomyocytes, were also reduced only in MI Endo myocytes. Conversely, in MI rats treated with the antioxidant N-acetylcysteine (NAC) for 4 weeks, the generation of superoxide anions in Endo cardiomyocytes was normalized and the contractile properties of skinned cardiomyocytes restored. This effect was accompanied by improved in vivo contractility. The beneficial effects of NAC were mediated, at least, in part, through reduction of the PKA activity, which was higher in MI myofilaments, particularly, the PKA-mediated hyperphosphorylation of cardiac Troponin I.
  
  
  METHODS
  The Transmural gradient in the mitochondrial content/activity is lost during HF and mediates reactive oxygen species-dependent contractile dysfunction.
  
  
  CONCLUSIONS
  Regionalized alterations in redox signaling affect the contractile machinery of sub-Endo myocytes through a PKA-dependent pathway that contributes to the loss of the transmural contractile gradient and impairs global contractility.
authors.affiliation: U1046, INSERM, Université Montpellier 1, Université Montpellier 2, Montpellier, France.
authors.forename: Lucas
authors.initials: L
authors.lastname: Andre
authors.forename: Jeremy
authors.initials: J
authors.lastname: Fauconnier
authors.forename: Cyril
authors.initials: C
authors.lastname: Reboul
authors.forename: Christine
authors.initials: C
authors.lastname: Feillet-Coudray
authors.forename: Pierre
authors.initials: P
authors.lastname: Meschin
authors.forename: Charlotte
authors.initials: C
authors.lastname: Farah
authors.forename: Gilles
authors.initials: G
authors.lastname: Fouret
authors.forename: Sylvain
authors.initials: S
authors.lastname: Richard
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
authors.forename: Olivier
authors.initials: O
authors.lastname: Cazorla
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D002118:Calcium / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D015227:Lipid Peroxidation; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009210:Myofibrils / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D000242:Cyclic AMP; D002374:Catalase; D013482:Superoxide Dismutase; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium; D000111:Acetylcysteine