Zhang Ping, Liu Yuanyuan, Zhan Yuliang, Zou Pengtao, Cai Xinyong, Chen Yanmei, Shao Liang
Department of Neurology, Jiangxi Provincial People's Hospital, The First Hospital Affiliated to Nanchang Medical College, Nanchang, Jiangxi, China.
Department of Cardiology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital to Nanchang Medical College, Nanchang, Jiangxi, China.
Epigenetics. 2024 Dec;19(1):2380145. doi: 10.1080/15592294.2024.2380145. Epub 2024 Jul 17.
Doxorubicin (DOX)-mediated cardiotoxicity can impair the clinical efficacy of chemotherapy, leading to heart failure (HF). Given the importance of circRNAs and miRNAs in HF, this paper intended to delineate the mechanism of the circular RNA 0006332 (circ -0,006,332)/microRNA (miR)-143/Toll-like receptor 2 (TLR2) axis in doxorubicin (DOX)-induced HF. The binding of miR-143 to circ -0,006,332 and TLR2 was assessed with the dual-luciferase assay, and the binding between miR-143 and circ -0,006,332 was determined with FISH, RIP, and RNA pull-down assays. miR-143 and/or circ -0,006,332 were overexpressed in rats and cardiomyocytes, followed by DOX treatment. In cardiomyocytes, miR-143 and TLR2 expression, cell viability, LDH release, ATP contents, and levels of IL-1β, IL-18, TNF-α, and pyroptosis-related molecules were examined. In rats, cardiac function, serum levels of cardiac enzymes, apoptosis, myocardial fibrosis, and levels of IL-1β, IL-18, TNF-α, TLR2, and pyroptosis-related molecules were detected. miR-143 diminished TLR2 expression by binding to TLR2, and circ -0,006,332 bound to miR-143 to downregulate miR-143 expression. miR-143 expression was reduced and TLR2 expression was augmented in DOX-induced cardiomyocytes. miR-143 inhibited DOX-induced cytotoxicity by suppressing pyroptosis in H9C2 cardiomyocytes. In DOX-induced rats, miR-143 reduced cardiac dysfunction, myocardial apoptosis, myocardial fibrosis, TLR2 levels, and pyroptosis. Furthermore, overexpression of circ -0,006,332 blocked these effects of miR-143 on DOX-induced cardiomyocytes and rats. Circ -0,006,332 stimulates cardiomyocyte pyroptosis by downregulating miR-143 and upregulating TLR2, thus promoting DOX-induced cardiac injury.
阿霉素（DOX）介导的心脏毒性会损害化疗的临床疗效，导致心力衰竭（HF）。鉴于环状RNA（circRNAs）和微小RNA（miRNAs）在HF中的重要性，本文旨在阐明环状RNA 0006332（circ -0,006,332）/微小RNA（miR）-143/Toll样受体2（TLR2）轴在阿霉素（DOX）诱导的HF中的作用机制。采用双荧光素酶报告基因检测法评估miR-143与circ -0,006,332和TLR2的结合，并通过荧光原位杂交（FISH）、RNA免疫沉淀（RIP）和RNA下拉实验确定miR-143与circ -0,006,332之间的结合。在大鼠和心肌细胞中过表达miR-143和/或circ -0,006,332，随后进行DOX处理。检测心肌细胞中miR-143和TLR2的表达、细胞活力、乳酸脱氢酶（LDH）释放、三磷酸腺苷（ATP）含量以及白细胞介素-1β（IL-1β）、白细胞介素-18（IL-18）、肿瘤坏死因子-α（TNF-α）和焦亡相关分子的水平。在大鼠中，检测心脏功能、血清心肌酶水平、细胞凋亡、心肌纤维化以及IL-1β、IL-18、TNF-α、TLR2和焦亡相关分子的水平。miR-143通过与TLR2结合降低TLR2的表达，circ -0,006,332与miR-143结合下调miR-143的表达。在DOX诱导的心肌细胞中，miR-143表达降低，TLR2表达增加。miR-143通过抑制H9C2心肌细胞中的焦亡来抑制DOX诱导的细胞毒性。在DOX诱导的大鼠中，miR-143减轻心脏功能障碍、心肌细胞凋亡、心肌纤维化、TLR2水平和焦亡。此外，circ -0,006,332的过表达阻断了miR-143对DOX诱导的心肌细胞和大鼠的这些作用。Circ -0,006,332通过下调miR-143和上调TLR2刺激心肌细胞焦亡，从而促进DOX诱导的心脏损伤。
