Sulfaphenazole attenuates myocardial cell apoptosis accompanied with cardiac ischemia-reperfusion by suppressing the expression of BimEL and Noxa.
We previously reported the administration of a potent cytochrome P450 inhibitor, sulfaphenazole (SPZ), to suppress oxidative stress and the extension of myocardial infarct size in a rat model of cardiac ischemia-reperfusion (I/R). The aim of this study was to investigate the effects of SPZ on the myocardial cell apoptosis induced by I/R in rats. I/R injury was evoked by ligation of the left anterior descending coronary artery for 1 h, followed by reperfusion for 3 h. TUNEL-positive nuclei were detected and nucleosomal DNA fragmentation was observed 3 h after reperfusion. The administration of SPZ largely suppressed the cardiac DNA fragmentation induced by I/R. A pan-caspase inhibitor, z-VAD-fmk, had no effect on DNA fragmentation. Caspase-3/7 was not activated 3 h after reperfusion. Decreases in the mitochondrial membrane potential and cytochrome c release from the mitochondria to cytosol were detected 3 h after reperfusion. The expression levels of BimEL and Noxa were elevated 3 h after reperfusion. These phenomena were suppressed by the administration of SPZ. Taken together, treatment with SPZ could attenuate the myocardial cell apoptosis accompanied with I/R by inhibiting the mitochondrial dysfunction due to decreases in the expression of BimEL and Noxa.
Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8521, Japan. ishiyasu@hiroshima-u.ac.jp
Yasuhiro
Y
Ishihara
Norio
N
Shimamoto
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013426:Sulfaphenazole / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D008565:Membrane Proteins; C539472:Pmaip1 protein, rat; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013426:Sulfaphenazole; D045304:Cytochromes c; D053148:Caspase 3; D053179:Caspase 7