Autophagic degradation of CCN2 (cellular communication network factor 2) causes cardiotoxicity of sunitinib
Autophagic degradation of CCN2 (cellular communication network factor 2) causes cardiotoxicity of sunitinib
复制标题
DOI：
10.1080/15548627.2021.1965712
复制
发表时间：
2021-08
期刊：
影响因子：
13.3
通讯作者：
Zhifei Xu;Yixiao Jin;Zizheng Gao;Y. Zeng;Jiangxia Du;Hao Yan;Xueqin Chen;Li Ping;Nengming L
中科院分区：
文献类型：
--
作者：
Zhifei Xu;Yixiao Jin;Zizheng Gao;Y. Zeng;Jiangxia Du;Hao Yan;Xueqin Chen;Li Ping;Nengming L
摘要自噬是心血管疾病或癌症治疗引起心肌细胞死亡的原因之一，但其机制尚不清楚。本课题组和其他研究小组先前报道了自噬可能参与了临床上广泛使用的肿瘤血管生成抑制剂舒尼替尼引起的心肌细胞死亡，这可能有助于理解自噬诱导心肌细胞死亡的机制。在这里，我们发现舒尼替尼诱导的自噬导致心肌细胞凋亡和心功能障碍，因为心肌细胞特异性Atg 7 −/+杂合子小鼠对舒尼替尼耐药。舒尼替尼诱导的适应不良自噬选择性降解心肌细胞存活介质CCN 2（蜂窝通信网络因素2）通过TOLLIP（toll相互作用蛋白）介导的内体相关途径和通过腺相关病毒血清型9（AAV 9）对Ccn 2的心肌细胞特异性敲低模拟舒尼替尼诱导的体内心功能障碍，提示CCN 2的自噬降解是舒尼替尼诱导的心肌毒性和心肌细胞死亡的原因之一。值得注意的是，HMGB 1（高迁移率族蛋白1）的缺失抑制了舒尼替尼诱导的心肌细胞自噬和凋亡，HMGB 1特异性抑制剂烟酸（GA）显著减轻了舒尼替尼诱导的自噬、心肌细胞死亡和心脏毒性。我们的研究揭示了一种新的自噬降解靶蛋白在心肌细胞死亡的调节，并强调了HMGB 1的药理学抑制剂作为一种有吸引力的方法，以提高安全性的舒尼替尼为基础的癌症治疗。
ABSTRACT Excessive macroautophagy/autophagy is one of the causes of cardiomyocyte death induced by cardiovascular diseases or cancer therapy, yet the underlying mechanism remains unknown. We and other groups previously reported that autophagy might contribute to cardiomyocyte death caused by sunitinib, a tumor angiogenesis inhibitor that is widely used in clinic, which may help to understand the mechanism of autophagy-induced cardiomyocyte death. Here, we found that sunitinib-induced autophagy leads to apoptosis of cardiomyocyte and cardiac dysfunction as the cardiomyocyte-specific Atg7 −/+ heterozygous mice are resistant to sunitinib. Sunitinib-induced maladaptive autophagy selectively degrades the cardiomyocyte survival mediator CCN2 (cellular communication network factor 2) through the TOLLIP (toll interacting protein)-mediated endosome-related pathway and cardiomyocyte-specific knockdown of Ccn2 through adeno-associated virus serotype 9 (AAV9) mimics sunitinib-induced cardiac dysfunction in vivo, suggesting that the autophagic degradation of CCN2 is one of the causes of sunitinib-induced cardiotoxicity and death of cardiomyocytes. Remarkably, deletion of Hmgb1 (high mobility group box 1) inhibited sunitinib-induced cardiomyocyte autophagy and apoptosis, and the HMGB1-specific inhibitor glycyrrhizic acid (GA) significantly mitigated sunitinib-induced autophagy, cardiomyocyte death and cardiotoxicity. Our study reveals a novel target protein of autophagic degradation in the regulation of cardiomyocyte death and highlights the pharmacological inhibitor of HMGB1 as an attractive approach for improving the safety of sunitinib-based cancer therapy.