The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, P. R. China.
Department of Pharmacology, The Key Laboratory of Pharmacology and Toxicology for New Drugs, Hebei Medical University, Shijiazhuang, P. R. China.
J Biochem Mol Toxicol. 2023 Aug;37(8):e23393. doi: 10.1002/jbt.23393. Epub 2023 Jul 6.
Doxorubicin (DOX), an effective and broad-spectrum anthracycline antibiotic, is widely used in the treatment of numerous malignancies. However, dose-dependent cardiotoxicity limits the clinical application of DOX, and the molecular mechanisms are still unknown. In this study, we used the BK receptor B1/B2 double-knockout (B1B ) mice to observe the role of BK receptor in cardiotoxicity induced by DOX and the underlying mechanisms. DOX induced myocardial injury with increased serum levels of AST, CK, and LDH, upregulated tissue expression of bradykinin B1/B2 receptor, FABP4 and iNOS, and downregulated expression of eNOS. However, these altered releases of myocardial enzyme and the expression level of iNOS were significantly prevented in the B1B2 mice. We concluded that the activation of both B1 and B2 receptors of BK were involved in the DOX-induced acute myocardial injury, possibly mediated through iNOS signaling pathways.
多柔比星（DOX）是一种有效且广谱的蒽环类抗生素，广泛用于治疗多种恶性肿瘤。然而，剂量依赖性心脏毒性限制了 DOX 的临床应用，其分子机制尚不清楚。在本研究中，我们使用 BK 受体 B1/B2 双敲除（B1B2）小鼠观察 BK 受体在 DOX 诱导的心脏毒性中的作用及其潜在机制。DOX 诱导心肌损伤，导致血清中天冬氨酸转氨酶（AST）、肌酸激酶（CK）和乳酸脱氢酶（LDH）水平升高，组织中缓激肽 B1/B2 受体、脂肪酸结合蛋白 4（FABP4）和诱导型一氧化氮合酶（iNOS）表达上调，内皮型一氧化氮合酶（eNOS）表达下调。然而，在 B1B2 小鼠中，这些心肌酶的释放变化和 iNOS 的表达水平明显受到抑制。综上，BK 受体的 B1 型和 B2 型均被激活参与了 DOX 诱导的急性心肌损伤，可能通过 iNOS 信号通路介导。
