The involvement and therapeutic potential of lncRNA Kcnq1ot1/miR-34a-5p/Sirt1 pathway in arsenic trioxide-induced cardiotoxicity

Abstract

Abstract Background/Aims Arsenic trioxide (ATO) is the first-line therapeutic drug for acute promyelocytic leukemia. However, the cardiotoxicity of ATO limits its clinical application. This study aims to explore the long noncoding RNA (lncRNA) involved molecular mechanism in ATO-induced cardiotoxicity and to identify available prevention strategies. Methods ATO was administered to mice or primary cultured mouse cardiomyocytes. Small interfering RNA targeting lncRNA Kcnq1ot1 (si-Kcnq1ot1) was used to knockdown lncRNA Kcnq1ot1. MiR-34a-5p mimic and antisense morpholino oligonucleotide targeting miR-34a-5p (AMO-34a-5p) were used to upregulate and downregulate the expression of miR-34a-5p, respectively. TUNEL staining was conducted to detect cell DNA damage. Flow cytometry assay was used to detect cell apoptosis. Western blot was conducted to detect Bcl-2, Bax and Sirt1 protein expression. Real-time PCR was used to detect lncRNA Kcnq1ot1, miR-34a-5p, and Sirt1 mRNA expression. Dual-luciferase reporter assay was performed to validate the predicted binding site. Results ATO induced apoptosis in cardiomyocytes both in vivo and in vitro. Simultaneously, the expression of lncRNA Kcnq1ot1 and Sirt1 was downregulated, and miR-34a-5p was upregulated. MiR-34a-5p has binding sites with lncRNA Kcnq1ot1 and Sirt1. Knockdown of lncRNA Kcnq1ot1 induced apoptosis of cardiomyocytes, with increased miR-34a-5p and decreased Sirt1 expression. Inhibition of miR-34a-5p attenuated si-Kcnq1ot1-induced apoptosis in cardiomyocytes. Therefore, the lncRNA Kcnq1ot1/miR-34a-5p/Sirt1 signaling pathway is involved in ATO-induced cardiotoxicity. Propranolol alleviated ATO-induced apoptosis in cardiomyocytes both in vivo and in vitro, which was related to the lncRNA Kcnq1ot1/miR-34a-5p/Sirt1 signaling pathway. Conclusion The lncRNA Kcnq1ot1/miR-34a-5p/Sirt1 pathway is involved in ATO-induced cardiotoxicity. Propranolol can attenuate ATO-induced cardiotoxicity at least partially through the lncRNA Kcnq1ot1/miR-34a-5p/Sirt1 pathway. Combined administration with propranolol may be a new strategy for alleviating the cardiotoxicity of ATO.

Keywords

• Arsenic trioxide
• Cardiotoxicity
• LncRNA Kncq1ot1
• Propranolol