Inhibition of miR-223 attenuates the NLRP3 inflammasome activation, fibrosis, and apoptosis in diabetic cardiomyopathy

Xu, Danning; Zhang, Xiuzhen; Chen, Xuan; Yang, Shufen; Chen, Hongmei

doi:10.1016/j.lfs.2020.117980

Cited by 43 publications

(30 citation statements)

References 46 publications

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“…Zhou et al confirmed that miR-495 suppressed the NLRP3 inflammasome signaling pathway by targeting NLRP3 3'-UTR (40). MiR-223 and miR-374a-5p were also found to have a negative regulatory effect on the activation of NLRP3 inflammatory signals (41,42). In addition, the expression of NLRP3 and IL-1β has proven to be regulated by NF-κB activation (43,44).…”

Section: Discussionmentioning

confidence: 98%

MicroRNA-146a-5p alleviates lipopolysaccharide-induced NLRP3 inflammasome injury and pro-inflammatory cytokine production via the regulation of TRAF6 and IRAK1 in human umbilical vein endothelial cells (HUVECs)

Hou¹,

Deng²,

Deng

et al. 2021

Ann Transl Med

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Background: Microribonucleic acids (miRNAs) have an evident role in regulating endothelial inflammation and dysfunction, which characterizes the early stages of atherosclerosis. The NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome has been reported to contribute to the endothelial inflammatory response that promotes atherosclerosis development and progression.This study sought to investigate the effects of miR-146a-5p on lipopolysaccharide (LPS)-induced NLRP3 inflammasome injury and pro-inflammatory cytokine production in human umbilical vein endothelial cells (HUVECs).Methods: HUVECs were transfected with a miR-146a-5p mimic, small-interfering RNA (siRNA) (si-TRAF6, and si-IRAK1), and were then stimulated with LPS for 24 h. The messenger (mRNA) and the protein levels of p-NF-κB/NF-κB, NLRP3, Caspase-1, pro-inflammatory cytokine [interleukin (IL)-6, IL-1β and tumor necrosis factor alpha (TNF-α)] in the HUVECs were analyzed by quantitative real-time polymerase chain reactions (PCRs) and western blot assays, respectively. The secretion of IL-6 from the cells was detected by enzyme-linked immunoassay (ELISA). Bioinformatic and dual-luciferase reporter assays were performed to identify the targets of miR-146a-5p.Results: LPS promoted pro-inflammatory cytokine expression in a dose-dependent manner and significantly increased the expression levels of p-NF-κB/NF-κB p65, NLRP3, and Caspase-1. After transfection with a miR-146a-5p mimic, or si-TRAF6 or si-IRAK1, we observed that the mRNA and protein levels of NF-κB/p-NF-κB, NLRP3, Caspase-1, and pro-inflammatory cytokine in the HUVECs were all down-regulated, and the secretion of IL-6 from cells declined significantly. After transfection with a miR-146-5p mimic, the expression of TRAF6 and IRAK1 in HUVECs were both down-regulated. Dualluciferase reporter assays confirmed that miR-146-5p directly targets the 3'-untranslated region (3'-UTR) of TRAF6 and IRAK1 to regulate their expression.Conclusions: As a modulator of TRAF6 and IRAK1, miR-146a-5p negatively regulated LPS-induced NF-κB activation and the NLRP3 inflammasome signaling pathway in HUVECs. Thus, miRNA-146a-5p may serve as a potential therapeutic target for atherosclerosis.

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Section: Discussionmentioning

confidence: 98%

MicroRNA-146a-5p alleviates lipopolysaccharide-induced NLRP3 inflammasome injury and pro-inflammatory cytokine production via the regulation of TRAF6 and IRAK1 in human umbilical vein endothelial cells (HUVECs)

Hou¹,

Deng²,

Deng

et al. 2021

Ann Transl Med

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“…Shao et al revealed that the expression of miR-223-3p was higher in the serum and aqueous humor of DR patients as compared with that of nondiabetic subjects and miR-223-3p levels were consistent with the severity of DR, indicating that miR-223-3p could serve as a potential biomarker in the progression of DR (Shao et al, 2019). More recently, miR-223 was found to exert regulatory effects on diabetic cardiomyopathy (Deng et al, 2020;Xu D. et al, 2020). The role of miR-223-5p in DK has not been explored to date.…”

Section: Discussionmentioning

confidence: 99%

“…Of these miRNA/mRNA pairs mentioned above, miR-223-5p/ Hpgds attracted our attention due to the most significant shift of miR-223-5p. Moreover, miR-223 was reported to play a role in disorders induced by DM (Deng et al, 2020;Xu D. et al, 2020) and Hpgds can increase insulin sensitivity (Fujitani et al, 2010). 4E,F).…”

Section: Suppressing Mir-223-5p Promoted Diabetic Delayed Corneal Epithelial and Nerve Regenerationmentioning

confidence: 99%

Transcriptional Network Analysis Reveals the Role of miR-223-5p During Diabetic Corneal Epithelial Regeneration

Zhang

Dou

et al. 2021

Front. Mol. Biosci.

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Diabetes mellitus (DM) is a complex metabolic disorder. Long-term hyperglycemia may induce diabetic keratopathy (DK), which is mainly characterized by delayed corneal epithelial regeneration. MicroRNAs (miRNAs) have been reported to play regulatory roles during tissue regeneration. However, the molecular mechanism by which miRNAs influence epithelial regeneration in DK is largely unknown. In this study, we performed miRNA and mRNA sequencing of regenerative corneal epithelium tissue from streptozotocin-induced type 1 diabetic (T1DM) and wild-type mice to screen for differentially expressed miRNAs and mRNAs. Based on regulatory network analysis, miR-223-5p was selected for subsequent experiments and Hpgds was then identified as a direct target gene. MiR-223-5p downregulation significantly promoted diabetic corneal epithelial wound healing and nerve regeneration. However, the beneficial effects of miR-223-5p inhibition were abolished by an Hpgds inhibitor. Furthermore, mechanistic studies demonstrated that miR-223-5p suppression ameliorated inflammation and enhanced cell proliferation signaling in DK. Taken together, our findings revealed that the regulatory role of miR-223-5p in diabetic corneal epithelial and nerve regeneration by mediating inflammatory processes and cell proliferation signaling. And silencing miR-223-5p may contribute to the development of potential therapeutic strategies for DK.

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“…The high risks of cardiovascular diseases have attracted much attention in diabetic patients [31,32]. Long-term hyperglycemia is supposed to induce damage and cause subsequent apoptosis in cardiomyocytes [33,34]. It has been reported that cardiomyocyte apoptosis exacerbated the development of DCM [35][36][37].…”

Section: Discussionmentioning

confidence: 99%

Melatonin alleviates hyperglycemic-induced cardiomyocyte apoptosis via regulation of long non-coding RNA H19/miR-29c/MAPK axis in diabetic cardiomyopathy

Tang

Zhong

Liu

et al. 2021

Preprint

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BackgroundRecent studies revealed that non-coding RNAs (ncRNAs) play a crucial role in pathophysiological processes involving diabetic cardiomyopathy that contributes to heart failure. The present study was designed to further investigate the anti-apoptotic effect of melatonin on cardiomyocyte in diabetic condition and to elucidate the potential mechanisms associated with ncRNAs. MethodsIn vivo, langendorff-perfusion system and histology staining were used to assess the effect of melatonin on cardiac function. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to measure the expression of ncRNAs. Protein expression levels were assessed by western bolt analysis. In vitro, hoechst 33258 staining and western bolt analysis were used to evaluate the effect of melatonin on apoptosis. We preformed luciferase assay and RNA immunoprecipitation to determine the targets of ncRNAs. RT-qPCR was used to observe the expression of ncRNAs in cardiomyocyte with high glucose treatment.ResultsIn animal models, our results indicated that melatonin notably alleviated cardiac dysfunction and mitigated cardiomyocyte apoptosis in diabetic rats. Interestingly, lncRNA H19 level was increased along with concomitant decrease of miR-29c level in diabetic rats. However, we demonstrated that melatonin significantly downregulated H19 level and upregulated miR-29c level in vivo. In vitro experiments, it has been verified that positive modulation of miR-29c and inhibition of lncRNA H19 as well as mitogen-activated protein kinase (MAPK) pathways distinctly attenuated apoptosis in high glucose-treated H9c2 cells. Luciferase activity assay was conducted to evaluate the potential target sites of miR-29c on lncRNA H19 and MAPK13. LncRNA H19 silencing signiﬁcantly downregulated the expression of the miR-29c target gene MAPK13 via inducing miR-29c expression. Furthermore, MAPK signal pathways were also affected through regulation of H19 and miR-29c. Most importantly, our results showed that melatonin alleviated hyperglycemic-induced cardiomyocyte apoptosis via inhibiting lncRNA H19/MAPK and increasing miR-29c level in vitro.ConclusionsThese results elucidate a novel protective mechanism of melatonin on diabetic cardiomyocyte apoptosis, which associated with the effect of melatonin on lncRNA H19/miR-29c expression and its downstream MAPK signal pathways, providing a promising strategy for preventing DCM in diabetic patients.

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Inhibition of miR-223 attenuates the NLRP3 inflammasome activation, fibrosis, and apoptosis in diabetic cardiomyopathy

Cited by 43 publications

References 46 publications

MicroRNA-146a-5p alleviates lipopolysaccharide-induced NLRP3 inflammasome injury and pro-inflammatory cytokine production via the regulation of TRAF6 and IRAK1 in human umbilical vein endothelial cells (HUVECs)

MicroRNA-146a-5p alleviates lipopolysaccharide-induced NLRP3 inflammasome injury and pro-inflammatory cytokine production via the regulation of TRAF6 and IRAK1 in human umbilical vein endothelial cells (HUVECs)

Transcriptional Network Analysis Reveals the Role of miR-223-5p During Diabetic Corneal Epithelial Regeneration

Melatonin alleviates hyperglycemic-induced cardiomyocyte apoptosis via regulation of long non-coding RNA H19/miR-29c/MAPK axis in diabetic cardiomyopathy

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