Zordoky Beshay N, Radin M Judith, Heller Lois, Tobias Anthony, Matise Ilze, Apple Fred S, McCune Sylvia A, Sharkey Leslie C
Department of Experimental and Clinical Pharmacology, University of Minnesota, 308 Harvard St S.E., Minneapolis, MN, 55455, USA.
Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Road, Columbus, OH, 43210, USA.
Cardiooncology. 2016;2:4. doi: 10.1186/s40959-016-0013-3. Epub 2016 Mar 15.
Doxorubicin (DOX) is a very effective anticancer medication that is commonly used to treat hematological malignancies and solid tumors. Nevertheless, DOX is known to have cardiotoxic effects that may lead to cardiac dysfunction and failure. In experimental studies, female animals have been shown to be protected against DOX-induced cardiotoxicity; however, the evidence of this sexual dimorphism is inconclusive in clinical studies. Therefore, we sought to investigate whether genetic background could influence the sexual dimorphism of DOX-induced cardiotoxicity.
Male and female Wistar Kyoto (WKY) and Spontaneous Hypertensive Heart Failure (SHHF) rats were used. DOX was administered in eight doses of 2 mg/kg/week and the rats were followed for an additional 12 weeks. Cardiac function was assessed by trans-thoracic echocardiography, systolic blood pressure was measured by the tail cuff method, and heart and kidney tissues were collected for histopathology.
Female sex protected against DOX-induced weight loss and increase in blood pressure in the WKY rats, whereas it protected against DOX-induced cardiac dysfunction and the elevation of cardiac troponin in SHHF rats. In both strains, female sex was protective against DOX-induced nephrotoxicity. There was a strong correlation between DOX-induced renal pathology and DOX-induced cardiac dysfunction.
This study highlights the importance of studying the interaction between sex and genetic background to determine the risk of DOX-induced cardiotoxicity. In addition, our findings suggest that DOX-induced nephrotoxicity may play a role in DOX-induced cardiac dysfunction in rodent models.
阿霉素（DOX）是一种非常有效的抗癌药物，常用于治疗血液系统恶性肿瘤和实体瘤。然而，已知DOX具有心脏毒性作用，可能导致心脏功能障碍和衰竭。在实验研究中，已表明雌性动物可免受DOX诱导的心脏毒性影响；然而，这种性别差异在临床研究中的证据尚无定论。因此，我们试图研究遗传背景是否会影响DOX诱导的心脏毒性的性别差异。
使用雄性和雌性Wistar Kyoto（WKY）大鼠和自发性高血压心力衰竭（SHHF）大鼠。以2mg/kg/周的剂量分八次给予DOX，并对大鼠再观察12周。通过经胸超声心动图评估心脏功能，通过尾袖法测量收缩压，并收集心脏和肾脏组织进行组织病理学检查。
雌性可保护WKY大鼠免受DOX诱导的体重减轻和血压升高，而在SHHF大鼠中，雌性可保护其免受DOX诱导的心脏功能障碍和心肌肌钙蛋白升高的影响。在这两种品系中，雌性均可保护大鼠免受DOX诱导的肾毒性。DOX诱导的肾脏病理与DOX诱导的心脏功能障碍之间存在很强的相关性。
本研究强调了研究性别与遗传背景之间的相互作用以确定DOX诱导的心脏毒性风险的重要性。此外，我们的研究结果表明，在啮齿动物模型中，DOX诱导的肾毒性可能在DOX诱导的心脏功能障碍中起作用。
