Life Science Research Center, University of South China, Hengyang 421001, China.
Acta Biochim Biophys Sin (Shanghai). 2013 Oct;45(10):817-26. doi: 10.1093/abbs/gmt082. Epub 2013 Jul 28.
Doxorubicin (DOX), a widely used anti-tumor drug, can give rise to severe cardiotoxicity by oxidative stress and cell apoptosis, which restricts its clinical application. α-Linolenic acid (ALA) has been shown to serve as a potent cardioprotective agent. The aim of this study was to explore the protective effects of ALA on DOX-induced cardiotoxicity and the underlying molecular mechanisms for this cardioprotection in rats. Rats were randomly divided into four groups and administrated with normal saline, ALA (500 µg/kg), DOX (2.5 mg/kg), or ALA (500 µg/kg) plus DOX (2.5 mg/kg) for 17 days. The results showed that DOX treatment significantly increased the heart weight/body weight, liver wet weight (WW)/dry weight (DW), lung WW/DW, serum levels of brain natriuretic peptide, creatine kinase-MB, lactate dehydrogenase, and cardiac troponin I, myocardial necrosis and myocardial malondialdehyde content, and induced the mRNA expression of Nrf2 in the nucleus, cleaved caspase-3, Bax, and superoxide dismutase (SOD). In addition, DOX led to a significant decrease in left ventricular end-diastolic volume, stroke volume, ejection fraction, SOD, glutathione-peroxidase, catalase, as well as the expression of Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm, phospho-AKT, phospho-ERK, and Bcl-2. Co-treatment with ALA significantly eliminated these changes induced by DOX except further reduction of Keap1 and elevation of Nrf2 and SOD mRNA. These results showed the cardioprotective effects of ALA on DOX-induced cardiotoxicity in rats. The mechanisms might be associated with the enhancement of antioxidant defense system through activating Keap1/Nrf2 pathway and anti-apoptosis through activating protein kinase B/extracellular signal regulated kinase pathway. Our results suggested a promising future of ALA-based preventions and therapies for myocardial damage after administration of DOX.
多柔比星（DOX）是一种广泛使用的抗肿瘤药物，通过氧化应激和细胞凋亡引起严重的心脏毒性，限制了其临床应用。α-亚麻酸（ALA）已被证明是一种有效的心脏保护剂。本研究旨在探讨 ALA 对 DOX 诱导的心脏毒性的保护作用及其在大鼠心脏保护中的潜在分子机制。大鼠随机分为四组，分别给予生理盐水、ALA（500μg/kg）、DOX（2.5mg/kg）或 ALA（500μg/kg）加 DOX（2.5mg/kg），连续给药 17 天。结果显示，DOX 处理显著增加了心脏重量/体重比、肝湿重（WW）/干重（DW）、肺 WW/DW、血清脑钠肽、肌酸激酶同工酶-MB、乳酸脱氢酶和心肌肌钙蛋白 I 水平，以及心肌坏死和丙二醛含量，并诱导核内 Nrf2、裂解的半胱天冬酶-3、Bax 和超氧化物歧化酶（SOD）的 mRNA 表达。此外，DOX 导致左心室舒张末期容积、每搏输出量、射血分数、SOD、谷胱甘肽过氧化物酶、过氧化氢酶以及细胞质中 Kelch 样 ECH 相关蛋白 1（Keap1）、磷酸化 AKT、磷酸化 ERK 和 Bcl-2 的表达显著降低。用 ALA 联合处理可显著消除 DOX 引起的这些变化，除了进一步降低 Keap1 和增加 Nrf2 和 SOD mRNA 水平。这些结果表明，ALA 对 DOX 诱导的大鼠心脏毒性具有保护作用。其机制可能与通过激活 Keap1/Nrf2 通路增强抗氧化防御系统和通过激活蛋白激酶 B/细胞外信号调节激酶通路抗细胞凋亡有关。我们的结果表明，ALA 具有应用于 DOX 给药后心肌损伤的预防和治疗的广阔前景。
