Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo 315000, China.
Health Science Center, Ningbo University, Ningbo 315000, China.
Int Immunopharmacol. 2024 Nov 15;141:113010. doi: 10.1016/j.intimp.2024.113010. Epub 2024 Aug 24.
Doxorubicin (DOX) is limited in clinical use due to its cardiotoxic side effects. Oxidative stress and inflammation are pivotal mechanisms underlying doxorubicin-induced cardiotoxicity (DIC). Sulfiredoxin 1 (Srxn1) plays a central role in antioxidant effects. However, the role of Srxn1 in DIC has not yet been fully elucidated. This study aims to explore the effects and underlying mechanisms of Srxn1 on DIC.
We overexpressed Srxn1 in the myocardium using an adeno-associated virus 9 (AAV9) system, delivered through tail vein injection. C57BL/6 mice received intraperitoneal injections of DOX (4 mg/kg) weekly for four consecutive weeks to establish a mouse model of DIC. We used echocardiography, histopathological, and molecular techniques to elucidate the effects and mechanisms.
Our findings demonstrate that overexpression of Srxn1 significantly enhanced cardiac function and mitigated myocardial injury in mice exposed to DOX. Overexpressing Srxn1 attenuated oxidative stress and inflammation induced by DOX. Furthermore, Srxn1 overexpression led to upregulation of sirtuin 1 (Sirt1) expression and inhibited the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome. Notably, the protective effects of Srxn1 were significantly abrogated by the Sirt1 inhibitor EX527.
The protective effects of Srxn1 against DOX-induced cardiac oxidative stress and inflammation operate by targeting the Sirt1/NLRP3 signaling pathway to alleviate DIC. Srxn1 could be a potential candidate for the treatment of DOX-induced myocardial injury.
多柔比星（DOX）由于其心脏毒性副作用，在临床应用中受到限制。氧化应激和炎症是多柔比星诱导的心脏毒性（DIC）的关键机制。硫氧还蛋白 1（Srxn1）在抗氧化作用中发挥核心作用。然而，Srxn1 在 DIC 中的作用尚未完全阐明。本研究旨在探讨 Srxn1 对 DIC 的影响及其潜在机制。
我们使用腺相关病毒 9（AAV9）系统通过尾静脉注射在心肌中过表达 Srxn1。C57BL/6 小鼠每周腹腔注射 DOX（4mg/kg），连续 4 周建立 DIC 小鼠模型。我们使用超声心动图、组织病理学和分子技术来阐明作用和机制。
我们的研究结果表明，过表达 Srxn1 可显著增强 DOX 暴露小鼠的心脏功能并减轻心肌损伤。过表达 Srxn1 可减轻 DOX 诱导的氧化应激和炎症。此外，Srxn1 过表达导致 Sirtuin 1（Sirt1）表达上调，并抑制 NOD 样受体蛋白 3（NLRP3）炎症小体的激活。值得注意的是，Sirt1 抑制剂 EX527 显著削弱了 Srxn1 的保护作用。
Srxn1 对 DOX 诱导的心脏氧化应激和炎症的保护作用通过靶向 Sirt1/NLRP3 信号通路发挥作用，从而减轻 DIC。Srxn1 可能是治疗 DOX 诱导的心肌损伤的潜在候选药物。
