LncRNA H19 suppresses pyroptosis of cardiomyocytes to attenuate myocardial infarction in a PBX3/CYP1B1-dependent manner
LncRNA H19 suppresses pyroptosis of cardiomyocytes to attenuate myocardial infarction in a PBX3/CYP1B1-dependent manner
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DOI：
10.1007/s11010-020-03998-y
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发表时间：
2021-01-03
影响因子：
4.3
通讯作者：
Yao, Chanjiao
中科院分区：
文献类型：
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作者：
Han, Youjian;Dong, Bo;Yao, Chanjiao
目的心肌梗死（myocardial infarction，MI）是心血管疾病的主要病因之一，给人们带来巨大的健康和经济负担。心肌梗死主要由缺氧引起。因此，本研究旨在探讨lncRNA H19在缺氧诱导的心肌细胞凋亡中的作用及其机制。方法收集正常对照组和心肌梗死患者外周血，测定H19和CYP 1B 1 mRNA和蛋白表达水平。分析了这两个因素之间的相关性。建立MI大鼠模型，注射H19过表达/CYP 1B 1敲低质粒，观察心肌梗死面积及病理形态学改变。用过表达或敲低的H19和CYP 1B 1转染低氧心肌细胞，以测定NLRP 3、ASC、caspase-1、IL-1 β、IL-18、CyclinD 1和PCNA。CCK 8法检测细胞增殖能力。应用RIP和双荧光素酶报告基因分析验证H19、PBX 3和CYP 1B 1之间的结合。结果MI患者H19表达下调，CYP 1B 1表达上调。H19和CYP 1B 1表达呈负相关。转染H19过表达或CYP 1B 1敲低基因可减轻MI大鼠的MI进程。在缺氧心肌细胞中，H19过表达或CYP 1B 1敲低除了抑制细胞凋亡率和促进细胞增殖率外，还可以抑制NLRP 3、ASC、caspase-1、IL-1 β和IL-18。在H19敲低和CYP 1B 1过表达的细胞中发现不同的表达模式。过表达CYP 1B 1可解除H19对心肌细胞凋亡的抑制作用。H19可通过调节PBX 3抑制CYP 1B 1启动子活性。结论H19可通过PBX 3依赖方式抑制CYP 1B 1的表达，从而减轻心肌细胞的细胞凋亡。
Objective Myocardial infarction (MI) is a major cause of cardiovascular disease which poses great healthy and financial burden for individuals. MI can be mainly induced by hypoxia. Therefore, in this study, we aimed to explore the function and mechanism of lncRNA H19 on hypoxia-induced pyroptosis of cardiomyocytes. Method Peripheral blood from healthy controls and MI patients was collected for determination of mRNA and protein expression levels of H19 and CYP1B1. The correlation between these two factors was analyzed. Then MI rat model was established and injected with H19 overexpression/CYP1B1 knockdown plasmid, in which the infraction area and pathological morphology were observed. Hypoxic cardiomyocytes were transfected with overexpression or knockdown of H19 and CYP1B1 for determination of NLRP3, ASC, caspase-1, IL-1 beta, IL-18, CyclinD1, and PCNA. Cell proliferation ability was assessed by CCK8. RIP and dual luciferase gene reporter assay were applied to verify the binding among H19, PBX3 and CYP1B1. Results Downregulated H19 and upregulated CYP1B1 were observed in MI patients. A negative correlation was found for H19 and CYP1B1 expressions. Transfection of H19 overexpression or CYP1B1 knockdown could attenuate the MI progression in MI rats. In hypoxic cardiomyocytes, H19 overexpression or CYP1B1 knockdown could also inhibit NLRP3, ASC, caspase-1, IL-1 beta, and IL-18 in addition to suppressing cell apoptosis rate and promoting cell proliferation rate. Different expression pattern was found in cells transfected with H19 knockdown or CYP1B1 overexpression. Overexpression of CYP1B1 could abrogate the suppressive effect of H19 on pyroptosis of cardiomyocytes. H19 could inhibit activity of CYP1B1 promoters by regulating PBX3. Conclusion H19 could inhibit CYP1B1 expression in a PBX3-dependent way and thus attenuate cell pyroptosis of cardiomyocytes.