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MiRs have impact on diabetic cardiac fibrosis. Numerous studies showed that the expression of miRs was upregulated and downregulated in diabetic cardiac fibrosis. These results indicated that miRs play a key role in diabetic cardiac fibrosis
Source publication
Purpose:
Diabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes, which further lead to heartfailure. It is known that diabetes-induced cardiac fibrosis is a key pathogenic factor contributing topathological changes in DCM. However, pathogenetic mechanisms underlying diabetes cardiac fibrosis arestill elusive. Recent studies ha...
Citations
... LcnRNAs are involved in the development of various disorders and have been linked to cardiovascular disease [17][18][19]. In epigenetics, DNA methylation affects not only LcnRNA expression but also myocardial fibrosis disease, which involves LcnRNA [20]. ...
... Recent new perspectives and advances have shown that lncRNAs exert effects on diabetic cardiac fibrosis progression 29 . The ultrastructure and myocardial histomorphological alterations are damaged, and myocardial collagen I and collagen III protein levels are increased in diabetic rats 30 . ...
Aims/introduction:
Fibrosis is the principle reason for heart failure in diabetes. Regarding the involvement of long non-coding ribonucleic acid zinc finger E-box binding homeobox 1 antisense 1 (ZEB1-AS1) in diabetic myocardial fibrosis, we explored its specific mechanism.
Materials and methods:
Human cardiac fibroblasts (HCF) were treated with high glucose (HG) and manipulated with plasmid cloning deoxyribonucleic acid 3.1-ZEB1-AS1/microribonucleic acid (miR)-181c-5p mimic/short hairpin RNA specific to sirtuin 1 (sh-SIRT1). ZEB1-AS1, miR-181c-5p expression patterns, cell viability, collagen I and III, α-smooth muscle actin (α-SMA), fibronectin levels and cell migration were assessed by reverse transcription quantitative polymerase chain reaction, cell counting kit-8, western blot and scratch tests. Nuclear/cytosol fractionation assay verified ZEB1-AS1 subcellular localization. The binding sites between ZEB1-AS1 and miR-181c-5p, and between miR-181c-5p and SIRT1 were predicted and verified by Starbase and dual-luciferase assays. The binding of SIRT1 to Yes-associated protein (YAP) and YAP acetylation levels were detected by co-immunoprecipitation. Diabetic mouse models were established. SIRT1, collagen I, collagen III, α-SMA and fibronectin levels, mouse myocardium morphology and collagen deposition were determined by western blot, and hematoxylin-eosin and Masson trichrome staining.
Results:
Zinc finger E-box binding homeobox 1 antisense 1 was repressed in HG-induced HCFs. ZEB1-AS1 overexpression inhibited HG-induced HCF excessive proliferation, migration and fibrosis, and diminished collagen I, collagen III, α-SMA and fibronectin protein levels in cells. miR-181c-5p had targeted binding sites with ZEB1-AS1 and SIRT1. SIRT1 silencing/miR-181c-5p overexpression abrogated ZEB1-AS1-inhibited HG-induced HCF proliferation, migration and fibrosis. ZEB1-AS1 suppressed HG-induced HCF fibrosis through SIRT1-mediated YAP deacetylation. ZEB1-AS1 and SIRT1 were repressed in diabetic mice, and miR-181c-5p was promoted. ZEB1-AS1 overexpression improved myocardial fibrosis in diabetic mice, and reduced collagen I, collagen III, α-SMA and fibronectin protein levels in myocardial tissues.
Conclusion:
Long non-coding ribonucleic acid ZEB1-AS1 alleviated myocardial fibrosis through the miR-181c-5p-SIRT1-YAP axis in diabetic mice.
... Notably, transforming growth factor (TGF)α-/EGFR interaction apparently promotes Phosphatidylinositol-3-kinase (PI3K)/Akt signaling, which then promotes nuclear factor κB (NF-κB), resulting in ICAM-1 production and stimulation of human osteogenic sarcoma cells' ability to migrate [109]. Changes in the lncRNAs and/or miRNAs expression have recently been found to impact the translation and stability of genes playing roles in the fibroblast activation process in the kidney [110], liver [111], lung [110,112], and heart [113,114]. Other ceRNA axes proposed to engage in inflammation and autoimmune response were LINC01820:13/has-miR-27b-3p/formyl peptide receptor 2 (FPR2) and the ENST00000499452/hsa-miR-27a-3p/C-X-C Motif Chemokine Ligand 1 (CXCL1) [76]. ...
... In opposed to LPAL2 knockdown, miR-1287-5p suppression boosted TGF-β1-induced OF hyperproliferation and raised adhesion molecules and collagen I protein expression [71]. Epigenetic studies have recently demonstrated that changes in the expression levels of lncRNAs and/or miRNAs can impact the stability and translation of genes implicated in the activation of fibroblast and fibrosis in the lung [110,112], kidney [110], liver [111], and heart [113,114]. ...
Abstract
Background
It is becoming more and more apparent that Grave's Ophthalmopathy (GO) pathogenesis may be aided by epigenetic processes such as DNA methylation modifications, histone tail covalent modifications, and non-coding RNA (ncRNA)-based epigenetic processes. In the present study, we aimed to focus more on the miRNAs rather than lncRNAs due to lack of investigations on these non-coding RNAs and their role in GO's pathogenesis.
Methods
A six-stage methodology framework and the PRISMA recommendation were used to conduct this scoping review. A comprehensive search was conducted across seven databases to discover relevant papers published until February 2022. The data extraction separately, and quantitative and qualitative analyses were conducted.
Results
A total of 20 articles were found to meet inclusion criteria. According to the results, ncRNA were involved in the regulation of inflammation (miR-146a, LPAL2/miR-1287–5p axis, LINC01820:13/hsa miR-27b-3p axis, and ENST00000499452/hsa-miR-27a-3p axis), regulation of T cell functions (miR-146a/miR-183/miR-96), regulation of glycosaminoglycan aggregation and fibrosis (miR-146a/miR-21), glucocorticoid sensitivity (miR-224–5p), lipid accumulation and adipogenesis (miR-27a/miR-27b/miR-130a), oxidative stress and angiogenesis (miR-199a), and orbital fibroblast proliferation (miR-21/miR-146a/miR-155). Eleven miRNAs (miR-146a/miR-224–5p/miR-Let7d-5p/miR-96–5p/miR-301a-3p/miR-21–5p) were also indicated to have the capacity to be used as biomarkers.
Conclusions
Regardless of the fact that there is significant documentation of ncRNA-mediated epigenetic dysfunction in GO, additional study is needed to thoroughly comprehend the epigenetic connections concerned in disease pathogenesis, paving the way for novel diagnostic and prognostic tools for epigenetic therapies among the patients.
Keywords
EpigeneticsGraves' ophthalmopathy (GO)Non-coding RNA (ncRNA)
... Such epigenetic modifications include DNA methylation, acetylation and methylation of histones. These modifications can alter the production of specific miRNAs and lncRNAs, which play important roles through regulation of gene expression at both transcriptional and translational levels [25]. Furthermore, a regulatory interaction exists between specific miRNA and lncRNA ANRIL [26]. ...
Diabetic cardiomyopathy (DCM) is one of the most prevalent causes of morbidity and mortality in diabetic patients. Hyperglycemia induces increased expression/deposition of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (Col) and plays an important role in fibrosis in diabetic cardiomyopathy (DCM). The roles of RNAs including microRNA (miRNA) and long non-coding RNAs (lncRNA) have begun to be understood in many conditions. In this study, we investigated the role of a specific miRNA, miR-9, and its interactions with lncRNA ZFAS1 in mediating fibrosis in DCM. Treatment with 25 mM glucose (HG) decreased miR-9 expression and increased expressions of ZFAS1, ECM proteins and inflammatory markers, compared to 5 mM glucose (NG) in the HCMECs by using qRT-PCR. Glucose-induced upregulation of ECM proteins can be prevented by ZFAS1 siRNA or miR-9 mimic transfection. Luciferase assay was confirmed miR-9 binding to FN 3'-UTR. miR-9 expression can be regulated by ZFAS1 through polycomb repressive complex 2 (PRC2) components using RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays. In the in vivo experiment, hyperglycemia-induced the ECM production can be prevented by the miR-9 overexpression in the fibrosis in DCM. These studies showed a novel glucose-induced molecular mechanism in which ZFAS1 participates in the transcriptional regulation of ECM protein production in diabetes through miR-9.
... However, many challenges in delivery and stability remain to be overcome in this approach (Ghosh and Katare, 2018). Development of ncRNA (miRNA and lncRNA) inhibitors or mimics involved in cardiac fibrosis may serve as ideal targets (Tao et al., 2018). ...
Diabetes mellitus is a common disease affecting millions of people worldwide. This disease is not limited to metabolic disorders but also affects several vital organs in the body and can lead to major complications. People with diabetes mellitus are subjected to cardiovascular complications, such as cardiac myopathy, which can further result in major complications such as diabetes-induced cardiac failure. The mechanism underlying diabetes-induced cardiac failure requires further research; however, several contributing factors have been identified to function in tandem, such as reactive oxygen species production, inflammation, formation of advanced glycation end-products, altered substrate utilisation by mitochondria, activation of the renin–angiotensin–aldosterone system and lipotoxicity. Genetic factors such as microRNAs, long noncoding RNAs and circular RNAs, as well as epigenetic processes such as DNA methylation and histone modifications, also contribute to complications. These factors are potential targets for developing effective new therapies. This review article aims to facilitate in depth understanding of these contributing factors and provide insights into the correlation between diabetes mellitus and cardiovascular complications. Some alternative targets with therapeutic potential are discussed to indicate favourable targets for the management of diabetic cardiomyopathy.
... Mechanically, EA mediates multiple signaling pathways, such as nuclear factor-kappa B (NF-κB), in ammatory signaling and non-coding RNA-modulated keap1/Nrf2 system [9, 10, 12]. microRNAs (miRs) are belonged to non-coding RNAs and are implicated in numerous physio-pathological progression [13][14][15]. miRs are responsible for the post-transcriptional repression of protein translation by binding with the 3'-untranslated regions (3'-UTRs) of target genes [14]. Increasing studies corroborate that abnormal miRs (miR-15b-5p, miR-133b, miR-200 and miR-320a) attribute to hyperglycemia-induced renal injury [16][17][18][19], suggesting that miR-related therapeutic drugs may become imperative therapeutic options for DN. ...
Objective
Ellagic acid (EA) as a multi-target bioactive compound has been reported to improve diabetes-related complications, including diabetic nephropathy (DN). Herein, we plan to investigate the molecular mechanism underlying EA-mediated renal protection in diabetic mice.
Methods
Streptozotocin (STZ; 35 mg/kg successive injection for 5 times) was applied to establish DN model in mice. Normal or diabetic mice were administrated by EA (100 mg/kg/day) by intragastric administration for 8 weeks. In vitro diabetic cell model, podocytes and renal tubular epithelial cells (RTECs) were exposed to normal glucose (NG; 5 mM) or high glucose (HG; 30 mM).
Results
Our results demonstrated that EA treatment prevented HG-induced podocyte and RTEC apoptosis and growth inhibition by inhibiting NF-κB/miR-150-3p to activate BCL2 in vitro. In vivo diabetic model of mice, EA administration improved renal filtration function, tubular and glomerular injury, and interstitial fibrosis. More importantly, supplementation of EA also suppressed NF-κB/miR-150-3p activation and accelerated BCL2 expression in the kidney of diabetic mice. In another experiment, miR-150-3p antagomir as a potential gene therapeutic choice has been validated to rescue hyperglycemia-induced renal dysfunction in mouse model. Taken together, in vitro and in vivo experimental measurements corroborate that EA modulates NF-κB/miR-150-3p/BCL2 cascade signaling to attenuate renal damage in diabetic models.
Conclusion
Our findings revealed that EA modulated the suppression of NF-κB/miR-150-3p to activate BCL2 that contributed to prevent hyperglycemia-induced renal dysfunction. In addition, synthetic miR-150-3p antagomir or inhibitors could alleviate tubular injury and interstitial fibrosis, and prevent HG-induced podocyte and RTEC apoptosis.
... The miRNAs bind to target messenger RNAs (mRNAs) in a sequence-specific manner (18), whereas lncRNAs modulate gene expression by a number of different mechanisms, including their action as endogenous sponges for other RNA types, like mRNAs and miRNAs (25). Recently, epigenetic research has revealed that alterations in the expression of lncRNAs and/or miRNAs can affect the stability and translation of genes involved in fibroblast activation and fibrosis in the lung (26,27), kidney (28), liver (29), and heart (30,31). Therefore, in the present study we attempted to analyze differentially expressed lncRNAs and miRNAs that are related to cell adhesion factor signaling, and can affect orbital fibroblast activation and fibrosis in TED. ...
Background and aims
The activation of orbital fibroblasts, the prime targets in thyroid eye disease, is central to its underlying pathogenesis. We aimed to investigate the mechanism of thyroid eye disease orbital fibroblast activation from the perspective of non-coding RNA regulation.
Methods
Immunofluorescence (IF) staining was applied to evaluate the fibrotic changes in target cells. Cell proliferation were evaluated by EDU and colony formation assays. Collagen I concentration was determined by ELISA assay. Human microarray analysis was performed on three thyroid eye disease and 3 healthy control orbital tissue samples.
Results
Bioinformatics analysis showed that cell adhesion signaling factors were differentially expressed in thyroid eye disease tissues, including I-CAM-1, I-CAM-4, V-CAM, and CD44, which were all upregulated in diseased orbital tissues. LncRNA LPAL2 level was also upregulated in orbital tissues and positively correlated with I-CAM-1 and I-CAM-4 expression. Stimulation of the thyroid eye disease orbital fibroblasts by TGF-β1 significantly increased the expression of I-CAM-1, I-CAM-4, and LPAL2. Knockdown of LPAL2 in orbital fibroblasts inhibited TGF-β1-induced increases in cell adhesion factor levels and orbital fibroblast activation. Microarray profiling was performed on thyroid eye disease and normal orbital tissues to identify differentially expressed miRNAs and miR-1287-5p was remarkably reduced within diseased orbital samples. miR-1287-5p was directly bound to EGFR 3’UTR and LPAL2 and LPAL2 modulated EGFR/AKT signaling through targeting miR-1287-5p.
Conclusions
The LPAL2/miR-1287-5p axis modulated TGF-β1-induced increases in cell adhesion factor levels and thyroid eye disease orbital fibroblast activation through EGFR/AKT signaling.
... DM currently affects more than 371 million people worldwide and greatly threatens people's lives (1). In patients with DM, diabetic cardiomyopathy (DCM) is a serious diabetic cardiovascular complication, leading to more than half of DM-related mortality cases (2). The main features of DCM are myocardial fibrosis, ventricular enlargement and cardiac dysfunction, which can ultimately result in heart failure (3). ...
In recent years, diabetes mellitus has become a global issue with increasing incidence rate worldwide. Diabetic cardiomyopathy (DCM), one of the important complications of diabetes, refers to patients with type 1 and type 2 diabetes who have ventricular hypertrophy, fibrosis and even diastolic dysfunction. The pathogenesis of DCM is related to oxidative stress, inflammatory response, apoptosis, autophagy, myocardial fibrosis and, diabetic microangiopathy. Long non-coding RNAs (lncRNA) is a non-coding RNA with a length longer than 200 nucleotides which lack the ability of protein coding. With the development of molecular technology, massive evidence demonstrates that lncRNA play a critical role in the molecular mechanism of DCM. Moreover, it can also be used as potential diagnostic markers for DCM. In this review, we intend to summarize the pathological roles and molecular mechanism of lncRNA in the progression of diabetic cardiomyopathy, which may provide promising diagnosis and treatment strategies for DCM.
... Therefore, miRNAs are key regulatory factors in myocardial fibrosis-related diseases. We hypothesized that miRNAs may serve as a new therapeutic target and potential biomarker for cardiovascular diseases [9,10]. ...
Diabetic cardiomyopathy (DCM) is an important cardiac disorder in patients with diabetes. High glucose (HG) levels lead to inflammation of cardiomyocytes, oxidative stress, and long-term activation of autophagy, resulting in myocardial fibrosis and remodelling. Astragaloside-IV (AS-IV) has a wide range of pharmacological effects. This study aimed to investigate the effects of AS-IV on injury induced by HG in rat cardiomyocytes (H9C2(2-1)) and the involvement of the miR-34a-mediated autophagy pathway. An AS-IV concentration of 100 μM was selected based on H9C2(2-1) cell viability using the cell counting kit-8 (CCK-8). We found that 33 mM HG induced a morphologic change in cells and caused excessive oxidative stress, whereas AS-IV inhibited lipid peroxidation and increased superoxide dismutase activity. In terms of mRNA expression, HG increased miR-34a and inhibited Bcl2 and Sirt1, whereas AS-IV and miR-34a-inhibitor reversed the above effects. Further, LC3-GFP adenovirus infection and western blotting showed that HG increased autophagy, which was reversed synergistically by AS-IV and miR-34a-inhibitor. Bcl2 and pAKT/AKT protein expressions in the HG group was significantly lower than that in controls, but AS-IV and miR-34a-inhibitor antagonized the process. Thus, AS-IV inhibits HG-induced oxidative stress and autophagy and protects cardiomyocytes from injury via the miR-34a/Bcl2/(LC3II/LC3I) and pAKT/Bcl2/(LC3II/LC3I) pathways.
... Long non-coding RNAs (lncRNAs) are a subset of RNAs of over 200 nucleotides that play a key role in numerous biological processes [15]. In the past decades, lncRNAs have been intensely investigated and found to regulate diabetes and fibrosis progresses [16]. Blnc1 is a conserved lncRNA that could promote thermogenic gene expression in brown adipocytes [17]. ...
Background and objectives:
Diabetic nephropathy (DN) is one of the commonest microvascular complications of diabetes and has been the major cause of end-stage renal disease in many countries. It is of great clinical significance to further explore more efficacious therapeutic strategies for DN. This study aims to explore the effect of Blnc1 on renal fibrosis in diabetic nephropathy.
Methods:
In this study, mRNA level of Blnc1 was examined by RT-PCR. HE staining and Masson staining were adopted to detect kidney damage and renal fibrosis. The renal fibrosis was evaluated by the levels of PTEN, fibronectin, collagen I and collagen IV with immunofluorescence assay and western blot analysis. Oxidative Stress and inflammatory response were detected by ELISA assay. At the same time, western blot was performed to detect the proteins related to NRF2/HO-1 and NF-κB pathways.
Results:
Blnc1 has higher expression in serum of DN patients, STZ-induced DN model and HG-induced HK2 cells. Blnc1 interference significantly attenuated renal fibrosis, inflammation and oxidative stress via NRF2/HO-1 and NF-κB pathways.
Conclusion:
Our present study suggested that Blnc1 can affect inflammation, oxidative stress and renal fibrosis by Nrf2/HO-1 and NF-κB pathways in DN.
