Department of Neurology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006 Jiangxi, China.
Department of Cardiology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006 Jiangxi, China.
Oxid Med Cell Longev. 2023 Jan 24;2023:4938287. doi: 10.1155/2023/4938287. eCollection 2023.
Patients undergoing doxorubicin (Dox) chemotherapy often develop new-onset atrial fibrillation and heart failure. Recent studies indicate that the TLR4/MyD88/NLRP3 pyroptosis signaling pathway plays a key role in the occurrence and development of cancer, heart failure, and atherosclerosis. However, few studies investigated the role of oxidative stress and pyroptosis in doxorubicin-induced heart failure and new-onset atrial fibrillation. In this study, we recruited 84 healthy subjects, 112 patients undergoing Dox chemotherapy showing heart failure (HF), and 62 patients undergoing Dox treatment who manifested atrial fibrillation (AF). The mRNA and protein levels of TLR4 expression, several downstream pyroptosis-associated proteins (cleaved caspase-1, NLRP3, GSDMD-N, and HMGB-1), serum inflammatory factors, and oxidative stress were detected at the beginning of chemotherapy and after 3 months of Dox chemotherapy. Oxidative stress and downstream pyroptosis-associated proteins tended to increase in the Dox-baseline group to the Dox-HF group. However, virtually no change in the expression of either oxidative stress or pyroptosis-associated proteins was detected in patients after three months of Dox chemotherapy compared with those at baseline. This study suggests that the prolonged oxidative stress and high levels of pyroptosis-associated proteins contribute to cardiac systolic dysfunction, suggesting TLR4 as a novel biomarker and a potential treatment target for doxorubicin-induced heart failure.
接受多柔比星（Dox）化疗的患者常发生新发心房颤动和心力衰竭。最近的研究表明，TLR4/MyD88/NLRP3 焦亡信号通路在癌症、心力衰竭和动脉粥样硬化的发生和发展中起关键作用。然而，很少有研究探讨氧化应激和焦亡在多柔比星诱导的心力衰竭和新发心房颤动中的作用。在这项研究中，我们招募了 84 名健康受试者、112 名接受多柔比星化疗且表现出心力衰竭（HF）的患者和 62 名接受多柔比星治疗且表现出心房颤动（AF）的患者。在化疗开始时和多柔比星化疗 3 个月后，检测 TLR4 表达的 mRNA 和蛋白水平、几种下游焦亡相关蛋白（裂解的 caspase-1、NLRP3、GSDMD-N 和 HMGB-1）、血清炎症因子和氧化应激。在多柔比星基线组到多柔比星 HF 组中，氧化应激和下游焦亡相关蛋白的表达呈上升趋势。然而，与基线相比，多柔比星化疗 3 个月后患者的氧化应激或焦亡相关蛋白的表达几乎没有变化。本研究表明，氧化应激持续增加和焦亡相关蛋白水平升高导致心脏收缩功能障碍，提示 TLR4 可作为多柔比星诱导心力衰竭的新型生物标志物和潜在治疗靶点。
