Riley Heart Research Center, Wells Center for Pediatric Research, Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, Indiana 46202-5225, USA.
Am J Physiol Heart Circ Physiol. 2012 Apr 15;302(8):H1603-13. doi: 10.1152/ajpheart.00844.2011. Epub 2012 Feb 10.
Doxorubicin is a highly effective chemotherapeutic agent used for treating a wide spectrum of tumors, but its usage is limited because of its dose-dependent cardiotoxicity, especially in pediatric patients. Accumulating evidence indicates that caspase-dependent apoptosis contributes to the cardiotoxicity of doxorubicin. However, less attention has been paid to the effects of age on doxorubicin-induced apoptosis signaling in myocardium. This study focused on investigating differential apoptotic sensitivity between neonatal and adult myocardium, in particular, between neonatal and adult cardiomyocytes in vivo. Our results show that caspase-3 activity in normal mouse hearts decreased by ≥ 20-fold within the first 3 wk after birth, associated with a rapid downregulation in the expression of key proapoptotic proteins in intrinsic and extrinsic pathways. This rapid downregulation of caspase-3 activity was confirmed by immunostaining for cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP-mediated nick-end label staining. Doxorubicin treatment induced a dose-dependent increase in caspase-3 activity and apoptosis in neonatal mouse hearts, and both caspase-8 and caspase-9 activations were involved. Using transgenic mice with a nuclear localized LacZ reporter gene to label cardiomyocytes in vivo, we observed a fourfold higher level of doxorubicin-induced cardiomyocyte apoptosis in 1-wk-old mice compared with that in 3-wk-old mice. This study points to a major difference in apoptotic signaling in doxorubicin cardiotoxicity between neonatal and adult mouse hearts and reveals a critical transition from high to low susceptibility to doxorubicin-induced apoptosis during postnatal heart maturation.
多柔比星是一种高效的化疗药物，用于治疗广泛的肿瘤，但由于其剂量依赖性的心脏毒性，特别是在儿科患者中，其使用受到限制。越来越多的证据表明，半胱天冬酶依赖性细胞凋亡导致多柔比星的心脏毒性。然而，人们对年龄对多柔比星诱导的心肌细胞凋亡信号的影响关注较少。本研究集中于研究新生和成年心肌之间，特别是体内新生和成年心肌细胞之间的差异凋亡敏感性。我们的研究结果表明，正常小鼠心脏中的 caspase-3 活性在出生后 3 周内至少降低了 20 倍，伴随着内在和外在途径中关键促凋亡蛋白的表达迅速下调。通过免疫染色法检测裂解的 caspase-3 和末端脱氧核苷酸转移酶 dUTP 介导的缺口末端标记染色，证实了 caspase-3 活性的这种快速下调。多柔比星处理诱导新生小鼠心脏中 caspase-3 活性和凋亡呈剂量依赖性增加，涉及 caspase-8 和 caspase-9 的激活。利用体内标记心肌细胞的核定位 LacZ 报告基因的转基因小鼠，我们观察到 1 周龄小鼠的多柔比星诱导的心肌细胞凋亡水平比 3 周龄小鼠高 4 倍。这项研究指出了新生和成年小鼠心脏中多柔比星心脏毒性的凋亡信号之间的一个主要差异，并揭示了心脏成熟过程中从高到低对多柔比星诱导的凋亡敏感性的关键转变。
