title: The contribution of reactive oxygen species and p38 mitogen-activated protein kinase to myofilament oxidation and progression of heart failure in rabbits.
abstract: OBJECTIVE
  The formation of reactive oxygen species (ROS) is increased in heart failure (HF). However, the causal and mechanistic relationship of ROS formation with contractile dysfunction is not clear in detail. Therefore, ROS formation, myofibrillar protein oxidation and p38 MAP kinase activation were related to contractile function in failing rabbit hearts.
  
  
  RESULTS
  Three weeks of rapid left ventricular (LV) pacing reduced LV shortening fraction (SF, echocardiography) from 32 +/- 1% to 13 +/- 1%. ROS formation, as assessed by dihydroethidine staining, increased by 36 +/- 8% and was associated with increased tropomyosin oxidation, as reflected by dimer formation (dimer to monomer ratio increased 2.28 +/- 0.66-fold in HF vs. sham, P < 0.05). Apoptosis (TdT-mediated dUTP nick end labelling staining) increased more than 12-fold after 3 weeks of pacing when a significant increase in the phosphorylation of p38 MAP kinase and HSP27 was detected (Western blotting). Vitamins C and E abolished the increases in ROS formation and tropomyosin oxidation along with an improvement of LVSF (19 +/- 1%, P < 0.05 vs. untreated HF) and prevention of apoptosis, but without modifying p38 MAP kinase activation. Inhibition of p38 MAP kinase by SB281832 counteracted ROS formation, tropomyosin oxidation and contractile failure, without affecting apoptosis.
  
  
  CONCLUSIONS
  Thus, p38 MAP kinase activation appears to be upstream rather than downstream of ROS, which impacts on LV function through myofibrillar oxidation. p38 MAP kinase inhibition is a potential target to prevent or treat HF.
authors.affiliation: Institute of Pathophysiology, University of Essen Medical School, Essen, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Heusch
authors.forename: M
authors.initials: M
authors.lastname: Canton
authors.forename: S
authors.initials: S
authors.lastname: Aker
authors.forename: A
authors.initials: A
authors.lastname: van de Sand
authors.forename: I
authors.initials: I
authors.lastname: Konietzka
authors.forename: T
authors.initials: T
authors.lastname: Rassaf
authors.forename: S
authors.initials: S
authors.lastname: Menazza
authors.forename: O E
authors.initials: OE
authors.lastname: Brodde
authors.forename: F
authors.initials: F
authors.lastname: Di Lisa
authors.forename: G
authors.initials: G
authors.lastname: Heusch
authors.forename: R
authors.initials: R
authors.lastname: Schulz
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D001205:Ascorbic Acid / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D016503:Drug Delivery Systems; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016277:Ventricular Function, Left; D014810:Vitamin E / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C552886:(1,3-dihydroxyprop-2-yl)-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)imidazole; D000975:Antioxidants; D007093:Imidazoles; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D014810:Vitamin E; D048051:p38 Mitogen-Activated Protein Kinases; D001205:Ascorbic Acid