Bax ablation protects against myocardial ischemia-reperfusion injury in transgenic mice.
The role of the proapototic Bax gene in ischemia-reperfusion (I/R) injury was studied in three groups of mice: homozygotic knockout mice lacking the Bax gene (Bax(-/-)), heterozygotic mice (Bax(+/-)), and wild-type mice (Bax(+/+)). Isolated hearts were subjected to ischemia (30 min, 37 degrees C) and then to 120 min of reperfusion. The left ventricular developed force of Bax-deficient vs. Bax(+/+) hearts at stabilization and at 120 min of reperfusion was 1,411 +/- 177 vs. 1,161 +/- 137 mg and 485 +/- 69 vs. 306 +/- 68 mg, respectively. Superior cardiac function of Bax(-/-) hearts after I/R was accompanied by a decrease in creatine kinase release, caspase 3 activity, irreversible ischemic injury, and the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cardiomyocytes. Electron microscopic evaluation revealed reduced damage to mitochondria and the nuclear chromatin structure in Bax-deficient mice. In the Bax(+/-) hearts, the damage markers were moderate. The superior tolerance of Bax knockout hearts to I/R injury recommends this gene as a potential target for therapeutic intervention in patients with severe and intractable myocardial ischemia.
Hochhauser
Edith
E
Cardiac Research Laboratory, Department of Cardiothoracic Surgery, Tel Aviv University, Israel. hochhaus@post.tau.ac.il
Kivity
Shaye
S
Offen
Daniel
D
Maulik
Nilanjana
N
Otani
Hajime
H
Barhum
Yael
Y
Pannet
Hannah
H
Shneyvays
Vladymir
V
Shainberg
Asher
A
Goldshtaub
Valeri
V
Tobar
Anna
A
Vidne
Bernardo A
BA
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001696:Biomechanical Phenomena; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D019254:Genes, bcl-2 / Q000235:genetics; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009200:Myocardial Contraction / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D009336:Necrosis; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016277:Ventricular Function, Left / Q000502:physiology; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D003402:Creatine Kinase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases