Zhang Xiao-Juan, Cao Xiao-Qing, Zhang Chun-Sheng, Zhao Zhuo
Department of Cardiology, Shandong Provincial Chest Hospital, Jinan, Shandong 250013, P.R. China.
Department of Cardiology, Jinan Central Hospital Affiliated with Shandong University, Jinan, Shandong 250013, P.R. China.
Mol Med Rep. 2017 May;15(5):2695-2702. doi: 10.3892/mmr.2017.6332. Epub 2017 Mar 16.
Doxorubicin (DOX) is one of the most effective chemotherapeutic agents for the treatment of a number of malignancies. However, its use is limited by serious cardiotoxic effects, for which there are currently no reliable pharmacologic therapies. Estrogen has exhibited protective effects against cardiac stressors in male and female animal models; however, its effects on DOX‑induced cardiotoxicity remain unknown. High mortality and morbidity rates have been observed in patients with cancer worldwide, and DOX is often administered to a greater number of men than women. Therefore, the present study employed male Sprague-Dawley rats to evaluate the protective effects of 17β-estradiol (E2) against DOX-induced cardiotoxicity. A total of 4 mg/kg DOX was administered to 14‑week‑old male Sprague‑Dawley rats by intraperitoneal injection twice a week for 2 weeks. At 3 weeks following the first injection of DOX, an echocardiographic study revealed that DOX administration significantly decreased cardiac ejection fraction and fractional shortening by 20 and 29%, respectively, when compared with the vehicle‑treated control rats (P<0.05). This was associated with decreased heart weight, myofibrillar disorganization and myofiber loss. The serum biomarkers for heart injury, including alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and creatine kinase, were increased in DOX vs. vehicle‑treated rats (P<0.05). E2 treatment by a daily subcutaneous injection of 2 mg/kg body weight attenuated the cardiotoxic effects of DOX. In addition, E2 treatment inhibited the DOX‑induced increase in the expression of cardiac genes, nicotinamide adenine dinucleotide phosphate oxidase (NOX) 2, NOX4, B‑cell lymphoma 2‑associated X protein and caspase 3. These results demonstrate that E2 treatment may protect the heart against DOX-induced cardiotoxicity in male rats potentially through the regulation of NOX2, NOX4 and apoptosis genes.
阿霉素（DOX）是治疗多种恶性肿瘤最有效的化疗药物之一。然而，其应用受到严重心脏毒性作用的限制，目前尚无可靠的药物治疗方法。雌激素在雄性和雌性动物模型中已显示出对心脏应激源的保护作用；然而，其对DOX诱导的心脏毒性的影响仍不清楚。全世界癌症患者的死亡率和发病率都很高，接受DOX治疗的男性往往多于女性。因此，本研究采用雄性Sprague-Dawley大鼠来评估17β-雌二醇（E2）对DOX诱导的心脏毒性的保护作用。将总共4mg/kg的DOX通过腹腔注射给予14周龄的雄性Sprague-Dawley大鼠，每周两次，共2周。在首次注射DOX后3周，一项超声心动图研究显示，与接受赋形剂处理的对照大鼠相比，给予DOX显著降低了心脏射血分数和缩短分数，分别降低了20%和29%（P<0.05）。这与心脏重量减轻、肌原纤维紊乱和肌纤维损失有关。与接受赋形剂处理的大鼠相比，DOX处理的大鼠心脏损伤的血清生物标志物，包括丙氨酸转氨酶、天冬氨酸转氨酶、乳酸脱氢酶和肌酸激酶，均有所增加（P<0.05）。通过每日皮下注射2mg/kg体重的E2治疗减轻了DOX的心脏毒性作用。此外，E2治疗抑制了DOX诱导的心脏基因烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX）2、NOX4、B细胞淋巴瘤2相关X蛋白和半胱天冬酶3表达的增加。这些结果表明，E2治疗可能通过调节NOX2、NOX4和凋亡基因来保护雄性大鼠心脏免受DOX诱导的心脏毒性。
