Fas-Mediated Apoptosis in Adriamycin-Induced Cardiomyopathy in Rats

Ovid Technologies (Wolters Kluwer Health) - Tập 102 Số 5 - Trang 572-578 - 2000
Tsuneyuki Nakamura1, Yoshimichi Ueda1, Juan Yang1, Shogo Katsuda1, Hiroaki Takahashi1, Eikan Koh1
1From the Departments of Pediatrics (T.N., H.T., E.K.) and Pathology (Y.U., Y.J., S.K.), Kanazawa Medical University, Ishikawa, Japan.

Tóm tắt

Background —The precise molecular mechanism of Adriamycin-induced cardiomyopathy (ADR-CM) is still unknown. We address the demonstration of apoptotic myocardial cell death and the apoptosis-inducing molecules in ADR-CM induced in rats. Methods and Results —Until 8 weeks after the first administration of ADR, there was no increase in the number of labeled cells by terminal deoxynucleotidyl transferase assay (TUNEL method). Apoptotic indices increased significantly at weeks 9 and 10 in hearts of the ADR-treated group but not in those of the control group (0.42±0.12% versus 0.10±0.02% and 0.86±0.11% versus 0.09±0.04% at weeks 9 and 10, respectively). DNA ladder formation was also observed in the myocardial tissues during the late stages of the ADR-CM of rats. There was no significant difference in expression of p53 gene between the ADR group and the control group at either the message or the protein level. An overexpression of Fas antigen was shown in myocardial cells of ADR-treated hearts at weeks 9 and 10 by both Western blotting and immunofluorescent staining. Furthermore, we confirmed that neutralization of anti–Fas ligand antibody inhibited ADR-induced apoptosis. Conclusions —Apoptotic cell death was observed in the hearts of ADR-CM rats, and the number of apoptotic myocardial cells increased with the deterioration of morphological findings and cardiac function, indicating that apoptosis may be an important mechanism of loss of myocardial cells and cardiac dysfunction in ADR-CM. Apoptosis in ADR-CM rats is not p53-dependent but rather is executed through a Fas-mediated pathway.

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Tài liệu tham khảo

10.1056/NEJM197902083000610

10.1002/1097-0142(197308)32:2<302::AID-CNCR2820320205>3.0.CO;2-2

10.7326/0003-4819-91-5-710

Iliskovic N, Singal PK. Lipid lowering: an important factor in preventing adriamycin-induced heart failure. Am J Pathol. 1997;150:727–734.

Valdes Olmos RA ten Bokkei Huinink WW ten Hoeve RF et al. Assessment of anthracycline-related myocardial adrenergic derangement by (123I) metaiodobenzylguanidine scintigraphy. Eur J Cancer. 1995;31A:26–31.

10.1161/res.76.4.645

10.1016/0735-1097(95)00589-7

10.1073/pnas.87.11.4275

Majno G, Joris I. Apoptosis, oncosis, and necrosis: an overview of cell death. Am J Pathol. 1995;146:3–15.

10.1056/NEJM199610173351603

10.1056/NEJM199704173361603

10.1536/ihj.35.745

Itoh G, Tamura J, Suzuki M, et al. DNA fragmentation of human infarcted myocardial cells demonstrated by the nick end labeling method and DNA agarose gel electrophoresis. Am J Pathol. 1995;146:1325–1331.

Kajstura J, Cheng W, Reiss K, et al. Apoptotic and necrotic myocyte cell death are independent contributing variables of infarct size in rats. Lab Invest. 1996;74:86–107.

10.1161/circ.94.7.1506

10.1177/019262339402200109

10.1016/0003-2697(76)90526-1

Mettler FP, Young DM, Ward MJ. Adriamycin-induced cardiotoxicity (cardiomyopathy and congestive heart failure) in rats. Cancer Res. 1977;37:2705–2713.

10.1159/000401489

10.1161/circ.93.8.1588

Shrov VG, Sabbah HN, Shimoyama H, et al. Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure. Am J Pathol. 1996;148:141–149.

10.1172/JCI117504

10.1161/res.75.3.7520371

10.1016/0165-6147(92)90077-J

Resnicoff M, Braham D, Yutanawiboonchai W, et al. The insulin-like growth factor I receptor protects tumor cells from apoptosis in vivo. Cancer Res. 1995;55:2463–2469.

Liebermann DA, Hoffman B, Steinman R. Molecular control of growth arrest and apoptosis: p53-dependent and independent pathways. Oncogene. 1995;11:199–210.

10.1016/0092-8674(93)90509-O

10.1016/0092-8674(95)90412-3

10.1038/356314a0

10.1016/0092-8674(91)90614-5

10.1084/jem.169.5.1747

10.1126/science.7533326

Fulda S, Susin SA, Kroemer G, et al. Molecular ordering of apoptosis induced by anticancer drugs in neuroblastoma cells. Cancer Res. 1998;58:4453–4460.

10.1038/nm0596-574

Fulda S, Sieverts H, Friesen C, et al. The CD95 (APO-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells. Cancer Res. 1997;57:3823–3829.

10.1172/JCI119174

10.1074/jbc.272.35.22307

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Ovid Technologies (Wolters Kluwer Health)

Tập 102 Số 5

572-578

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