title: Apoptotic pathway activation from mitochondria and death receptors without caspase-3 cleavage in failing human myocardium: fragile balance of myocyte survival?
abstract: OBJECTIVE
  Activation of the caspase cascade through the mitochondrial and/or death receptor pathway was investigated in the failing human myocardium, in which the mode and extent of the cascade activation are unknown.
  
  
  BACKGROUND
  In terminal heart failure, a loss of cardiomyocytes by overload-induced apoptosis is an attractive mechanism, explaining the progressive character of the disease. However, its relevance is unclear, because the specificity of probes for apoptotic deoxyribonucleic acid damage is under debate.
  
  
  METHODS
  Left ventricular specimens from 36 explanted failing and 21 nonfailing donor hearts were used for messenger ribonucleic acid detection by semiquantitative reverse-transcription polymerase chain reaction. From these groups, immunoblot analysis was performed in samples from nine failing and six nonfailing donor hearts.
  
  
  RESULTS
  In terminally failing hearts, there was a significant accumulation of cytochrome c in the cytosol, which was associated with activation of caspase-9 and downregulation of its inhibitor, caspase-9S. Similarly, the death receptor-induced pathway revealed activation of caspase-8, combined with downregulation of its inhibitors, flice-like inhibitory protein-L (FLIP(L)) and FLIP(S). The unspecific caspase inhibitors, XIAP, hIAP-1 and hIAP-2, were also downregulated. However, the terminal effector caspase-3 was not activated, and its substrate gelsolin, acting in its uncleaved form as a feedback inhibitor of caspase-3, was not cleaved.
  
  
  CONCLUSIONS
  In the terminally failing human myocardium, the caspase cascade is partially activated in the presence of a consistent phenotype shift toward enhanced susceptibility to apoptosis. Although the system is still under a fragile control, the partial initiation of the apoptotic program may be of functional relevance also for the surviving cardiomyocytes.
authors.affiliation: Clinic for Cardiothoracic Surgery, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany. robert.scheubel@medizin.uni-halle.de
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Scheubel
authors.forename: Babett
authors.initials: B
authors.lastname: Bartling
authors.forename: Andreas
authors.initials: A
authors.lastname: Simm
authors.forename: Rolf Edgar
authors.initials: RE
authors.lastname: Silber
authors.forename: Kostas
authors.initials: K
authors.lastname: Drogaris
authors.forename: Dorothea
authors.initials: D
authors.lastname: Darmer
authors.forename: Juergen
authors.initials: J
authors.lastname: Holtz
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051033:Apoptosis Inducing Factor; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000187:drug effects / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D003580:Cytochromes / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology*; D004792:Enzyme Precursors / Q000187:drug effects / Q000378:metabolism; D005420:Flavoproteins / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D011506:Proteins; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism
chemical_list: C494829:AIFM1 protein, human; D000319:Adrenergic beta-Antagonists; D051033:Apoptosis Inducing Factor; D003580:Cytochromes; D004792:Enzyme Precursors; D005420:Flavoproteins; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins; D008565:Membrane Proteins; D011506:Proteins; D012333:RNA, Messenger; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases