LncRNA KCNQ1OT1 Mediates Pyroptosis in Diabetic Cardiomyopathy
LncRNA KCNQ1OT1 Mediates Pyroptosis in Diabetic Cardiomyopathy
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LncRNA KCNQ1OT1 介导糖尿病心肌病焦亡
DOI：
10.1159/000494576
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Wang, Lihong
中科院分区：
文献类型：
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作者：
Yang, Fan;Qin, Ying;Wang, Lihong
背景/目的：糖尿病心肌病（DCM）是糖尿病常见的并发症，可引起心力衰竭、心律失常和猝死。DCM的发病机制包括代谢改变、线粒体功能障碍、氧化应激、炎症、细胞死亡和细胞外基质重塑。最近，焦亡，一种与炎症相关的程序性细胞死亡，被证明在DCM中被激活。然而，DCM中焦亡的分子机制仍然难以捉摸。长链非编码RNA（lncRNA）Kcnq 1 ot 1参与多种心血管疾病。本研究旨在阐明Kcnq 1 ot 1是否影响DCM的心脏焦亡。方法：用5.5和50 mmol/L葡萄糖孵育AC 16细胞和原代心肌细胞。用链脲佐菌素（STZ）诱导糖尿病小鼠。Kcnq 1 ot 1在体外和体内均被沉默。qRT-PCR检测Kcnq 1 ot 1的表达水平。采用免疫荧光、qRT-PCR和western blot分析来检测焦亡的程度。采用超声心动图、苏木精-伊红染色、Masson三色染色等方法检测心脏功能和形态学变化。采用TUNEL染色、免疫荧光染色和Ca 2+测定检测细胞死亡和功能。结果：Kcnq 1 ot 1在糖尿病患者、高糖诱导的心肌细胞和糖尿病小鼠心肌组织中表达增强。沉默Kcnq 1 ot 1通过靶向miR-214- 3 p和caspase-1减轻细胞凋亡。此外，沉默Kcnq 1 ot 1减少细胞死亡，细胞骨架结构异常和钙超载在体外和改善心脏功能和形态在体内。结论：Kcnq 1 ot 1在DCM中过表达，沉默Kcnq 1 ot 1可通过影响miR-214- 3 p和caspase-1的表达抑制细胞凋亡。我们首次阐明Kcnq 1 ot 1可能是DCM的新治疗靶点。(C)2018作者（S）由S发布。Karger AG，巴塞尔
Background/Aims: Diabetic cardiomyopathy (DCM) is a common complication of diabetes and can cause heart failure, arrhythmia and sudden death. The pathogenesis of DCM includes altered metabolism, mitochondrial dysfunction, oxidative stress, inflammation, cell death and extracellular matrix remodeling. Recently, pyroptosis, a type of programmed cell death related to inflammation, was proven to be activated in DCM. However, the molecular mechanisms underlying pyroptosis in DCM remain elusive. The long non-coding RNA (lncRNA) Kcnq1ot1 participates in many cardiovascular diseases. This study aims to clarify whether Kcnq1ot1 affects cardiac pyroptosis in DCM. Methods: AC16 cells and primary cardiomyocytes were incubated with 5.5 and 50 mmol/L glucose. Diabetic mice were induced with streptozotocin (STZ). Kcnq1ot1 was silenced both in vitro and in vivo. qRT-PCR was used to detect the expression level of Kcnq1ot1. Immunofluorescence, qRT-PCR and western blot analyses were used to detect the degree of pyroptosis. Echocardiography, hematoxylin and eosin staining, and Masson's trichrome staining were used to detect the cardiac function and morphology in mice. Cell death and function were detected using TUNEL staining, immunofluorescence staining and Ca2+ measurements. Results: The expression of Kcnq1ot1 was increased in patients with diabetes, high glucose-induced cardiomyocytes and diabetic mouse cardiac tissue. Silencing Kcnq1ot1 alleviated pyroptosis by targeting miR-214-3p and caspase-1. Furthermore, silencing Kcnq1ot1 reduced cell death, cytoskeletal structure abnormalities and calcium overload in vitro and improved cardiac function and morphology in vivo. Conclusion: Kcnq1ot1 is overexpressed in DCM, and silencing Kcnq1ot1 inhibits pyroptosis by influencing miR-214-3p and caspase-1 expression. We clarified for the first time that Kcnq1ot1 could be a new therapeutic target for DCM. (C) 2018 The Author(s) Published by S. Karger AG, Basel