Downregulation of Long Non-Coding RNA Kcnq1ot1: An Important Mechanism of Arsenic Trioxide-Induced Long QT Syndrome

Jiang, Yanan; Du, Weijie; Chu, Qun; Qin, Ying; Tuguzbaeva, Gulnara; Wang, Hui; Li, Anqi; Li, Guiyang; Li, Yanyao; Chai, Lu; Yue, Er; Sun, Xi; Wang, Zhiguo; Pavlov, V. N.; Yang, Baofeng; Bai, Yunlong

doi:10.1159/000486357

Cited by 46 publications

(29 citation statements)

References 34 publications

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“…The sequence of the shRNA is GGTAGAATAGTTCTGTCTT. Then, 1 × 10 9 TU lentivirus-shRNA was dissolved in 50 μL saline and injected into the tail vein of diabetic mice 31 . All mice were kept for 8 weeks and were anesthetized by avertin.…”

Section: Methodsmentioning

confidence: 99%

Silencing long non-coding RNA Kcnq1ot1 alleviates pyroptosis and fibrosis in diabetic cardiomyopathy

et al. 2018

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Diabetes cardiomyopathy (DCM) is a critical complication of long-term chronic diabetes mellitus and is characterized by myocardial fibrosis and myocardial hypertrophy. It has been suggested that DCM is related to pyroptosis, a programmed cell death associated with inflammation. The long non-coding RNA Kcnq1ot1 is involved in different pathophysiological mechanisms of multiple diseases, including acute myocardial damage and arrhythmia. Our previous study found that Kcnq1ot1 was elevated in left ventricular tissue of diabetic mice. However, whether Kcnq1ot1 is capable of regulating pyroptosis and fibrosis in high glucose-treated cardiac fibroblasts remains unknown. The aim of the study was to investigate the mechanisms of Kcnq1ot1 in DCM. Our study revealed that silencing Kcnq1ot1 by a lentivirus-shRNA improved cardiac function and fibrosis, ameliorated pyroptosis, and inhibited TGF-β1/smads pathway in C57BL/6 mice. In vitro, experiments revealed that Kcnq1ot1 and pyroptosis were activated in cardiac fibroblasts treated with 30 mmol/l glucose. Furthermore, Kcnq1ot1 knockdown by a small interfering RNA decreased caspase-1 expression. Bioinformatic prediction and luciferase assays showed that Kcnq1ot1 functioned as a competing endogenous RNA to regulate the expression of caspase-1 by sponging miR-214-3p. In addition, silencing Kcnq1ot1 promoted gasdermin D cleavage and the secretion of IL-1β, thus repressing the TGF-β1/smads pathway in high glucose-treated cardiac fibroblasts through miR-214-3p and caspase-1. Therefore, Kcnq1ot1/miR-214-3p/caspase-1/TGF-β1 signal pathway presents a new mechanism of DCM progression and could potentially be a novel therapeutic target.

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Section: Methodsmentioning

confidence: 99%

Silencing long non-coding RNA Kcnq1ot1 alleviates pyroptosis and fibrosis in diabetic cardiomyopathy

et al. 2018

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“…Primary cardiomyocytes were extracted from the hearts of one-to three-dayold neonatal C57BL/6 mice. The isolation and culture methods were described previously [15]. The cells were cultured with 5.5 mM glucose (Control) or 50 mM glucose (HG) for 24 hours in Dulbecco's modified Eagle's medium (DMEM) (HyClone, Logan, UT, USA) supplemented with 10% fetal bovine serum (FBS) (Biological Industries, Beit-Haemek, Israel) at 37°C and 5% CO 2 .…”

Section: Immunohistochemical Analysismentioning

confidence: 99%

“…The lncRNA Kcnq1ot1, the full name of which is KCNQ1 overlapping transcript 1, is located in the KCNQ1 locus at 11p15.5 [13]. Kcnq1ot1 has been reported to be associated with many disorders, particularly those related to heart disease [14][15][16][17]. Li et al [14] indicated that suppression of Kcnq1ot1 might prevent myocardial I/R injury following acute myocardial infarction via regulating AdipoR1.…”

Section: Introductionmentioning

confidence: 99%

“…Li et al [14] indicated that suppression of Kcnq1ot1 might prevent myocardial I/R injury following acute myocardial infarction via regulating AdipoR1. Jiang et al [15] elucidated that silencing Kcnq1ot1 could regulate QT interval prolongation via inhibiting Kcnq1 gene expression. These researches demonstrated that Kcnq1ot1 plays a significant role in the heart, but the expression and mechanisms of Kcnq1ot1 in DCM are still unknown.…”

Section: Introductionmentioning

confidence: 99%

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LncRNA KCNQ1OT1 Mediates Pyroptosis in Diabetic Cardiomyopathy

Yang

Qin

Wang

et al. 2018

Cell Physiol Biochem

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146

109

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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.

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“…KCNQ1OT1 silencing led to a reduced level of KCNQ1(Y. Jiang et al, 2018). Thus, the relationship between the genes in theKcnq1 cluster needs further evaluation.…”

mentioning

confidence: 99%

KCNQ1OT1 facilitates progression of non‐small‐cell lung carcinoma via modulating miRNA‐27b‐3p/HSP90AA1 axis

Dong

Yang²,

Qiu

et al. 2018

Journal Cellular Physiology

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Long noncoding RNA KCNQ1OT1 participates in the regulation of imprinted genes within the kcnq1 domain. But its roles in carcinogenesis and metastasis remain largely elusive. Herein, we evaluated its potential in non‐small‐cell lung cancer (NSCLC) progression. We demonstrated that the KCNQ1OT1 level was upregulated in NSCLC tissues and cell lines. High KCNQ1OT1 level correlated with poor overall and progression‐free survival in NSCLC patients. KCNQ1OT1 facilitated proliferation, migration, and invasion in H460 cells. Furthermore, knockdown of KCNQ1OT1 reduced the expression of HSP90AA1. KCNQ1OT1 presented a positive correlation with HSP90AA1 which predicted the tumor progression in NSCLC from The Cancer Genome Atlas database. Intriguingly, KCNQ1OT1 modulated HSP90AA1 expression by sponging miR‐27b‐3p. MiR‐27b‐3p counteracted the effect of KCNQ1OT1 on HSP90AA1 expression, H460 cell migration, and invasion. These data revealed a role for KCNQ1OT1 as an oncogene through miR‐27b‐3p/HSP90AA1 axis during NSCLC progression.

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Downregulation of Long Non-Coding RNA Kcnq1ot1: An Important Mechanism of Arsenic Trioxide-Induced Long QT Syndrome

Cited by 46 publications

References 34 publications

Silencing long non-coding RNA Kcnq1ot1 alleviates pyroptosis and fibrosis in diabetic cardiomyopathy

Silencing long non-coding RNA Kcnq1ot1 alleviates pyroptosis and fibrosis in diabetic cardiomyopathy

LncRNA KCNQ1OT1 Mediates Pyroptosis in Diabetic Cardiomyopathy

KCNQ1OT1 facilitates progression of non‐small‐cell lung carcinoma via modulating miRNA‐27b‐3p/HSP90AA1 axis

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