We have previously found that, following myocardial ischemia/reperfusion injury, isolated hearts from bax gene knockout mice [Bax(-/-)] exhibited higher cardioprotection than the wild-type. We here explore the effect of Bax(-/-), following myocardial infarction (MI) in vivo. Homozygotic Bax(-/-) and matched wild-type were studied. Mice underwent surgical ligation of the left anterior descending coronary artery (LAD). The progressive increase in left-ventricular end diastolic diameter, end systolic diameter, in Bax(-/-) was significantly smaller than in Bax(+/+) at 28 d following MI (p < 0.03) as seen by echocardiography. Concomitantly, fractional shortening was higher (35 +/- 4.1% and 27 +/- 2.5%, p < 0.001) and infarct size was smaller in Bax(-/-) compared to the wild-type at 28 days following MI (24 +/- 3.7 % and 37 +/- 3.3%, p < 0.001). Creatine kinase and lactate dehydrogenase release in serum were lower in Bax(-/-) than in Bax(+/+) 24 h following MI. Caspase 3 activity was elevated at 2 h after MI only in the wild-type, but reduced to baseline values at 1 and 28 d post-MI. Bax knockout mice hearts demonstrated reduced infarct size and improved myocardial function following permanent coronary artery occlusion. The Bax gene appears to play a significant role in the post-MI response that should be further investigated.
Apoptosis appears to be a central mechanism of cell death following reperfusion of the ischemic liver. The aim of this study was to determine the effect of decreased expression of the proapoptotic Bax gene on hepatic apoptotic warm ischemia/reperfusion (I/R) injury. Three groups of mice were studied: homozygotic knockout mice (Bax Ϫ/Ϫ ); heterozygotic (Bax ϩ/Ϫ ); and wild type (Bax ϩ/ϩ ). Isolated mouse livers were subjected to 90 minutes of ischemia (37°C) followed by 15 minutes of reperfusion. Bax and Bcl-2 expression in liver tissue homogenates was measured by Western blot. Serum liver enzyme levels were measured and intrahepatic caspase-3 activity was determined by fluorimetric assay. Oil red O (ORO) staining was performed for fat detection. Apoptotic cells were identified by morphological criteria, immunohistochemistry for caspase-3, and terminal deoxynucleotidyl transferase-mediated 2Ј-deoxyuridine 5Ј-triphosphate nick-end labeling (TUNEL) assay. At 1 minute of reperfusion, the ischemic (Bax Ϫ/Ϫ ) livers were characterized by statistically significantly lower liver enzyme levels and lower caspase-3 activity than the ischemic (Bax ϩ/ϩ ) livers (P Ͻ 0.05 for both). The reduction in postischemic apoptotic hepatic injury in the ischemic Bax Ϫ/Ϫ livers group was confirmed morphologically, by the significantly reduced microvesicular steatosis as determined by ORO staining, fewer apoptotic hepatocyte cells detected (P Ͻ 0.05); immunohistochemically, by the significantly weaker activation of caspase-3 compared to the ischemic group (P Ͻ 0.05); and by TUNEL assay (P Ͻ 0.05). Similar levels of antiapoptotic Bcl-2 protein expression were detected in all 3 groups of ischemic livers on Western blots. Bax protein was not expressed in Bax-deficient livers and was detected in Bax ϩ/ϩ normal livers. In the Bax ϩ/Ϫ livers, levels of the damage markers were moderate. In conclusion, The better tolerance of Bax knockout livers to I/R injury suggests that the Bax gene may serve as a potential target for therapeutic intervention in hepatic I/R injury.
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