© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Effect of caspase inhibitors on myocardial infarct size and myocyte DNA fragmentation in the ischemia–reperfused rat heart
aSecond Department of Internal Medicine, Yamaguchi University School of Medicine, Yamaguchi, Japan
bSecond Department of Internal Medicine, Gifu, University School of Medicine, Gifu, Japan
* Corresponding author. Tel.: +81-836-22-2248; fax: +81-836-22-2246 masunori{at}po.cc.yamaguchi-u.ac.jp
Objective: Caspase family proteases are recognized as key mediators of apoptosis. However, the role of caspases in the ischemia–reperfused heart remains uncertain. We evaluated the effect of caspase inhibitors on myocardial infarct size and the myocyte DNA fragmentation in the ischemia–reperfused rat hearts. Methods: Three groups of Sprague–Dawley rats (n=7, each) were subjected to 30 min of ischemia followed by 6 h of reperfusion. One of the following drugs: (1) YVAD-aldehyde, a caspase-1-like protease inhibitor (3.5 mg/kg; YVAD), (2) DEVD-aldehyde, a caspase-3-like protease inhibitor (3.5 mg/kg, DEVD), (3) vehicle (140 µl/kg) was administered intravenously 5 min prior to the ischemia in each group. Myocardial infarct size was defined by triphenyltetrazolium chloride (TTC) staining. Immunohistochemical staining by in situ nick end labeling (TUNEL) of cardiomyocytes and DNA electrophoresis were used for detecting DNA fragmentation. Ultrastructural analysis was done by electron microscopy. The caspase activity was measured in the myocardium of both groups. Results: The percentage of TUNEL-positive myocyte nuclei (%AP) was quantified by microscopy. A ladder pattern was detected by electrophoresis of DNA from the risk area and TUNEL-positive myocytes were seen in the risk area. The %AP was significantly reduced from 20±1% to 12±3% by YVAD and to 10±3% by DEVD (both P<0.01). However, caspase inhibitors did not significantly change the infarct size. Electronmicrograph showed similar salcolemmal and mitochondrial damage in both group. The caspase activity was blocked by DEVD at 4 h after reperfusion. Conclusion: Myocyte DNA fragmentation and caspase activation was inhibited by caspase inhibitors without reduction of the infarct size in ischemia–reperfused rat hearts.
KEYWORDS Apoptosis; Infarction; Myocytes
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