Heat Shock Protein 22 Attenuates Doxorubicin-Induced Cardiotoxicity via Regulating Inflammation and Apoptosis
Heat Shock Protein 22 Attenuates Doxorubicin-Induced Cardiotoxicity via Regulating Inflammation and Apoptosis
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DOI：
10.3389/fphar.2020.00257
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发表时间：
2020-03-25
影响因子：
5.6
通讯作者：
Zeng, Qiutang
中科院分区：
文献类型：
--
作者：
Lan, Yin;Wang, Yi;Zeng, Qiutang
阿霉素(DOX)对心脏的急性和慢性毒性限制了其抗肿瘤作用，从而导致心脏损伤。热休克蛋白22(Hsp22)是一种在其他疾病和生理条件下具有抗细胞凋亡和抗炎作用的蛋白质。本研究旨在探讨HSP22在DOX所致心脏损伤中是否具有保护作用。方法用腺病毒载体介导HSP22的过表达，阐明HSP22在DOX所致心脏损伤中的作用。通过单次腹腔注射DOX(15 mg/kg)建立DOX致小鼠急性心脏损伤模型。随后，通过心脏染色和分子生物学分析，分析Hsp22在心脏损伤中的形态和生化作用。H9c2细胞用于体外验证。结果在DOX处理的心脏组织中观察到Hsp22的表达水平增加。此外，心脏特异的Hsp22过表达可减少DOX在体内和体外诱导的损伤心脏和心肌细胞的心功能障碍、炎症反应和细胞凋亡。此外，Hsp22对Toll样受体(TLR)4/NOD-、LRR-和吡咯结构域蛋白3(NLRP3)的抑制与Hsp22的保护作用有关。结论Hsp22过表达可通过阻断TLR4/NLRP3的活化来抑制DOX所致的心脏损伤。HSP22有望成为治疗肿瘤患者DOX所致心脏损伤的新方法。
BackgroundThe antitumor effect of doxorubicin (DOX) is limited by its acute and chronic toxicity to the heart, which causes heart injury. Heat shock protein 22 (Hsp22) is a protein proved to exert anti-apoptosis and anti-inflammatory effects in other diseases and physical conditions. In this study, we aim to explore whether Hsp22 could exert a protective role during cardiac injury in response to DOX.MethodsThe overexpression of Hsp22 was mediated via adenovirus vector to clarify the role of Hsp22 in the cardiac injury caused by DOX. DOX-induced acute heart injury mouse model was established by single intraperitoneal injection of DOX (15 mg/kg). Subsequently, cardiac staining and molecular biological analysis were performed to analyze the morphological and biochemical effects of Hsp22 on cardiac injury. H9c2 cells were used for validation in vitro.ResultsAn increase in the expression level of Hsp22 was observed in DOX-treated heart tissue. Furthermore, cardiac-specific overexpression of Hsp22 showed reduced cardiac dysfunction, decrease in inflammatory response, and reduction in cell apoptosis in injury heart and cardiomyocytes induced by DOX in vivo and in vitro. Moreover, the suppression of Toll-like receptor (TLR)4/NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) was associated with the protective effect of Hsp22. Finally, the protective effect of Hsp22 cardiac function was almost abolished by overexpression of NLRP3 in DOX-treated mice.ConclusionIn summary, Hsp22 overexpression in the heart could suppress cardiac injury in response to DOX treatment through blocking TLR4/NLRP3 activation. Hsp22 may become a new therapeutic method for treating cardiac injury induced by DOX in cancer patients.