Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
J Appl Toxicol. 2022 Feb;42(2):216-229. doi: 10.1002/jat.4203. Epub 2021 May 25.
Cyclosporin A (CsA) is a well-known and effective drug that is commonly used in autoimmune diseases and allotransplantation. However, kidney toxicity and cardiotoxicity limit its use. Circular RNAs (circRNAs) play a crucial role in disease, especially cardiovascular disease. We aimed to explore the circRNA expression profiles and potential mechanisms during CsA-induced cardiotoxicity. Sixty male adult Wistar rats were randomly divided into two groups. The CsA group was injected with CsA (15 mg/kg/day body weight) intraperitoneally (ip) for 2 weeks, whereas the control group was injected ip with the same volume of olive oil. We assessed CsA-induced cardiotoxicity by light microscopy, transferase-mediated dUTP nick-end labeling (TUNEL) staining, and electron microscopy. Microarray analysis was used to detect the expression profiles of circRNAs deregulated in the heart during CsA-induced cardiotoxicity. We confirmed the changes in circRNAs by quantitative PCR. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of the microarray data were performed. A conventional dose of CsA induced cardiotoxicity in rats. We identified 67 upregulated and 37 downregulated circRNAs compared with those in the control group. Six of 12 circRNAs were successfully verified by quantitative real-time polymerase chain reaction (qRT-PCR). GO analyses of the differentially expressed circRNAs indicated that these molecules might play important roles in CsA-induced cardiotoxicity. KEGG pathway analyses showed that the differentially expressed circRNAs in CsA-induced cardiotoxicity may be related to autophagy or the Hippo signaling pathway. We identified differential circRNA expression patterns and provided more insight into the mechanism of CsA-induced cardiotoxicity. CircRNAs may serve as potential biomarkers or therapeutic targets of CsA-mediated cardiotoxicity in the future.
环孢素 A（CsA）是一种众所周知且有效的药物，常用于自身免疫性疾病和同种异体移植。然而，肾毒性和心脏毒性限制了其应用。环状 RNA（circRNA）在疾病中发挥着至关重要的作用，尤其是心血管疾病。我们旨在探索环孢素 A 诱导的心脏毒性过程中的 circRNA 表达谱和潜在机制。
将 60 只成年雄性 Wistar 大鼠随机分为两组。CsA 组腹腔注射 CsA（15mg/kg/天体重）2 周，对照组腹腔注射相同体积的橄榄油。我们通过光镜、原位末端转移酶标记（TUNEL）染色和电子显微镜评估 CsA 诱导的心脏毒性。微阵列分析用于检测 CsA 诱导的心脏毒性过程中心脏中失调的 circRNA 表达谱。我们通过定量 PCR 验证了 circRNA 的变化。此外，还对微阵列数据进行了基因本体论（GO）和京都基因与基因组百科全书（KEGG）通路分析。
常规剂量的 CsA 可诱导大鼠心脏毒性。与对照组相比，我们鉴定出 67 个上调和 37 个下调的 circRNA。12 个 circRNA 中有 6 个通过实时定量聚合酶链反应（qRT-PCR）成功验证。差异表达 circRNA 的 GO 分析表明，这些分子可能在 CsA 诱导的心脏毒性中发挥重要作用。KEGG 通路分析表明，CsA 诱导的心脏毒性中差异表达的 circRNA 可能与自噬或 Hippo 信号通路有关。
我们鉴定了差异表达的 circRNA 模式，并为 CsA 诱导的心脏毒性机制提供了更多的见解。circRNA 可能成为未来 CsA 介导的心脏毒性的潜在生物标志物或治疗靶点。
