From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (H.Y.F., S.S., T.M., K.O., M.Y., S.T., R.A., Y.A., Y.S., T.M.); Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China (Y.L.); Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan (H.A.); Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan (M.A., M.K.); and Department of Biomedical Engineering, University of Virginia, Charlottesville (B.A.F.).
Circ Res. 2016 Mar 4;118(5):798-809. doi: 10.1161/CIRCRESAHA.115.307604. Epub 2016 Feb 1.
Doxorubicin is an effective chemotherapeutic agent for cancer, but its use is often limited by cardiotoxicity. Doxorubicin causes endoplasmic reticulum (ER) dilation in cardiomyocytes, and we have demonstrated that ER stress plays important roles in the pathophysiology of heart failure.
We evaluated the role of ER stress in doxorubicin-induced cardiotoxicity and examined whether the chemical ER chaperone could prevent doxorubicin-induced cardiac dysfunction.
We confirmed that doxorubicin caused ER dilation in mouse hearts, indicating that doxorubicin may affect ER function. Doxorubicin activated an ER transmembrane stress sensor, activating transcription factor 6, in cultured cardiomyocytes and mouse hearts. However, doxorubicin suppressed the expression of genes downstream of activating transcription factor 6, including X-box binding protein 1. The decreased levels of X-box binding protein 1 resulted in a failure to induce the expression of the ER chaperone glucose-regulated protein 78 which plays a major role in adaptive responses to ER stress. In addition, doxorubicin activated caspase-12, an ER membrane-resident apoptotic molecule, which can lead to cardiomyocyte apoptosis and cardiac dysfunction. Cardiac-specific overexpression of glucose-regulated protein 78 by adeno-associated virus 9 or the administration of the chemical ER chaperone 4-phenylbutyrate attenuated caspase-12 cleavage, and alleviated cardiac apoptosis and dysfunction induced by doxorubicin.
Doxorubicin activated the ER stress-initiated apoptotic response without inducing the ER chaperone glucose-regulated protein 78, further augmenting ER stress in mouse hearts. Cardiac-specific overexpression of glucose-regulated protein 78 or the administration of the chemical ER chaperone alleviated the cardiac dysfunction induced by doxorubicin and may facilitate the safe use of doxorubicin for cancer treatment.
多柔比星是一种有效的癌症化疗药物，但由于其心脏毒性，其应用常受到限制。多柔比星可导致心肌细胞内质网（ER）扩张，我们已经证明 ER 应激在心力衰竭的病理生理学中发挥重要作用。
我们评估 ER 应激在多柔比星诱导的心脏毒性中的作用，并研究化学 ER 伴侣是否可以预防多柔比星引起的心脏功能障碍。
我们证实多柔比星可导致小鼠心脏 ER 扩张，表明多柔比星可能影响 ER 功能。多柔比星激活了培养的心肌细胞和小鼠心脏中的 ER 跨膜应激传感器激活转录因子 6。然而，多柔比星抑制了激活转录因子 6 下游基因的表达，包括 X 盒结合蛋白 1。X 盒结合蛋白 1 的水平降低导致内质网伴侣葡萄糖调节蛋白 78 的表达受阻，葡萄糖调节蛋白 78 在 ER 应激的适应性反应中起着重要作用。此外，多柔比星激活了内质网膜驻留凋亡分子半胱氨酸天冬氨酸蛋白酶-12，这可导致心肌细胞凋亡和心脏功能障碍。腺相关病毒 9 介导的心脏特异性过表达葡萄糖调节蛋白 78 或化学 ER 伴侣 4-苯基丁酸的给药减轻了半胱氨酸天冬氨酸蛋白酶-12 的切割，缓解了多柔比星诱导的心脏凋亡和功能障碍。
多柔比星激活了 ER 应激起始的凋亡反应，但没有诱导 ER 伴侣葡萄糖调节蛋白 78，进一步增强了小鼠心脏的 ER 应激。心脏特异性过表达葡萄糖调节蛋白 78 或给予化学 ER 伴侣可减轻多柔比星引起的心脏功能障碍，并可能促进多柔比星安全用于癌症治疗。
