title: Inhibition of apoptosis by the intrinsic but not the extrinsic apoptotic pathway in myocardial ischemia-reperfusion.
abstract: CONCLUSIONS
  The detailed molecular mechanisms following activation of apoptosis in ischemia-reperfusion injury are unknown. This study using different transgenic mouse models provided first evidence that apoptosis in myocardial ischemia-reperfusion injury is rather linked to the mitochondrial pathway than to death receptor pathway.
  
  
  BACKGROUND
  There is a wealth of evidence for activation of apoptosis in ischemia-reperfusion injury. However, the understanding of detailed molecular mechanism is lacking.
  
  
  METHODS
  The extent of myocardial infarction after ligation of the left anterior descending artery in mice carrying different transgenes for inhibition of either the intrinsic or the extrinsic or a combination of both apoptotic cascades was evaluated. The extent of myocardial damage was assessed by echocardiographic determination of left ventricular (LV) ejection fraction, LV hemodynamics, troponin T, and histology. The rate of apoptosis was analyzed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and caspase-3 staining.
  
  
  RESULTS
  Highest perioperative rate of death was observed in the dominant-negative form of a truncated Fas-associated death domain (FADD-DN) group. Infarction size by 2,3,5-triphenyltetrazolium chloride (TTC) staining was smaller in the Bcl-2, but not in the other groups as compared to wild-type mice. This was accompanied by lower troponin T values in Bcl-2 transgenic mice as compared to the all other groups. Troponin T correlated well with macroscopic extent of myocardial infarction by TTC staining. A lower decline of LV ejection fraction was seen in the Bcl-2 as compared to wild-type or FADD-DN mice. A smaller number of TUNEL- and caspase-3-positive myocyte nuclei were observed in the Bcl-2 and FADD-DN group as compared to wild-type mice.
  
  
  CONCLUSIONS
  We provide first evidence for protective effects on the myocardium in a transgenic mouse model of myocardial ischemia-reperfusion due to inhibition of the Bcl-2, but not the FADD pathway despite that reduced apoptotic cells were observed in both groups as compared to wild-type mice.
authors: Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors: Arnt V
authors: AV
authors: Kristen
authors: Katrin
authors: K
authors: Ackermann
authors: Sebastian
authors: S
authors: Buss
authors: Lorenz
authors: L
authors: Lehmann
authors: Philipp A
authors: PA
authors: Schnabel
authors: Armin
authors: A
authors: Haunstetter
authors: Hugo A
authors: HA
authors: Katus
authors: Stefan E
authors: SE
authors: Hardt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism; D006439:Hemodynamics; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism / Q000473:pathology; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D013318:Stroke Volume; D020107:Troponin T / Q000378:metabolism; D016277:Ventricular Function, Left
chemical_list: D053200:Fas-Associated Death Domain Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D020107:Troponin T; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: Apoptosis; Bcl-2; Death receptors; FADD; Ischemia-reperfusion; Mitochondrion