Wang Jiawei, Fan Yixin, Cai Xiaomin, Gao Zhenzhen, Yu Zhengyi, Wei Bin, Tang Yulin, Hu Liang, Liu Wen-Tao, Gu Yanhong
Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Pharmacy, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.
Ann Transl Med. 2020 Dec;8(23):1570. doi: 10.21037/atm-20-3105.
Doxorubicin is an anthracycline antibiotic, which is effective for treating various malignancies such as leukemias and lymphomas. However, its serious cumulative dose-dependent cardiotoxicity limits its clinical application. Previous studies have shown that doxorubicin-associated cardiotoxicity is closely related to adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Uric acid is known to exert a strong antioxidant function and moderate protection on the nerves. However, its cardioprotective properties have not been established. This study aimed to investigate the potential effect of uric acid preconditioning on doxorubicin-induced cardiotoxicity and the involvement of AMPK signaling in this process.
An acute cardiotoxicity model of doxorubicin was established by intraperitoneal injection of a single dose of doxorubicin (20 mg/kg) in mice. Uric acid (62.5, 125, and 250 mg/kg) was intragastrically administered to mice one day before doxorubicin treatment and then continuously administered every 24 h for 8 consecutive days. The mortality rate and weight of the mice were recorded every day. Electrocardiograms (ECG) and serum biochemicals were detected with an ECG instrument and enzyme-linked immunosorbent assay kit (Elisa) respectively. A real-time cell analyzer (RTCA) was used to investigate the cytotoxicity of doxorubicin . Cell signaling was assayed by western blotting.
Uric acid (125 mg/kg) preconditioning increased the survival rate and body weight of doxorubicin-treated mice. Uric acid also effectively alleviated prolongation of the doxorubicin-induced QT interval, slowed heart rate, and reduced the plasma levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and creatine kinase (CK) in plasma in mice. Moreover, uric acid strongly activated AMPK and Src homology 2 domain-containing protein tyrosine phosphatase (SHP2), inhibiting doxorubicin-induced expression phosphorylated-c-Jun N-terminal kinases (JNK) and phosphorylated-connexin 43 (Cx43) and and effectively reversing the doxorubicin-induced decreased viability of H9C2 myocardial cells .
We demonstrated that uric acid preconditioning alleviated doxorubicin-induced cardiotoxicity through the AMPK-SHP2-JNK-Cx43 signaling pathway.
阿霉素是一种蒽环类抗生素，对治疗白血病和淋巴瘤等各种恶性肿瘤有效。然而，其严重的累积剂量依赖性心脏毒性限制了其临床应用。先前的研究表明，阿霉素相关的心脏毒性与5'-单磷酸腺苷（AMP）激活的蛋白激酶（AMPK）密切相关。已知尿酸具有强大的抗氧化功能，并对神经有适度的保护作用。然而，其心脏保护特性尚未得到证实。本研究旨在探讨尿酸预处理对阿霉素诱导的心脏毒性的潜在影响以及AMPK信号在此过程中的作用。
通过腹腔注射单剂量阿霉素（20 mg/kg）建立小鼠急性心脏毒性模型。在阿霉素治疗前一天对小鼠进行尿酸（62.5、125和250 mg/kg）灌胃，然后每24小时连续给药8天。每天记录小鼠的死亡率和体重。分别用心电图仪和酶联免疫吸附测定试剂盒（Elisa）检测心电图（ECG）和血清生化指标。使用实时细胞分析仪（RTCA）研究阿霉素的细胞毒性。通过蛋白质印迹法检测细胞信号。
尿酸（125 mg/kg）预处理提高了阿霉素处理小鼠的存活率和体重。尿酸还有效缓解了阿霉素诱导的QT间期延长、心率减慢，并降低了小鼠血浆中天冬氨酸转氨酶（AST）、乳酸脱氢酶（LDH）和肌酸激酶（CK）的水平。此外，尿酸强烈激活AMPK和含Src同源2结构域的蛋白酪氨酸磷酸酶（SHP2），抑制阿霉素诱导的磷酸化c-Jun氨基末端激酶（JNK）和磷酸化连接蛋白43（Cx43）的表达，并有效逆转阿霉素诱导的H9C2心肌细胞活力下降。
我们证明尿酸预处理通过AMPK-SHP2-JNK-Cx43信号通路减轻了阿霉素诱导的心脏毒性。
