Non-coding RNA-mediated endothelial-to-mesenchymal transition in human diabetic cardiomyopathy, potential regulation by DNA methylation
Abstract Aims Diabetic cardiomyopathy (DCM) is a major complication of diabetes and a risk factor for cardiovascular disease. Endothelial dysfunction is central to DCM, and endothelial-to-mesenchymal transition (EndMT) is a key form of endothelial dysfunction in diabetes. EndMT in DCM has been well-...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-11-01
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| Series: | Cardiovascular Diabetology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12933-023-02039-4 |
| _version_ | 1827770817676574720 |
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| author | Eric Wang Shali Chen Honglin Wang Tori Chen Subrata Chakrabarti |
| author_facet | Eric Wang Shali Chen Honglin Wang Tori Chen Subrata Chakrabarti |
| author_sort | Eric Wang |
| collection | DOAJ |
| description | Abstract Aims Diabetic cardiomyopathy (DCM) is a major complication of diabetes and a risk factor for cardiovascular disease. Endothelial dysfunction is central to DCM, and endothelial-to-mesenchymal transition (EndMT) is a key form of endothelial dysfunction in diabetes. EndMT in DCM has been well-studied in model systems and has been found to be epigenetically regulated by non-coding RNAs (ncRNAs). However, EndMT in DCM and its associated epigenetic changes need further characterization in human patients. It is also not known if ncRNAs are affected by changes in DNA methylation in DCM. This study aims to confirm in human hearts, the findings from animal and cell studies, and potentially provide novel insight into interactions between DNA methylation and ncRNAs in EndMT in DCM. Methods and results Heart tissues were collected from autopsy patients, fixed in formalin, and embedded in paraffin. Thin sections from paraffin-embedded tissues were used for histology and immunofluorescence analyses, where we confirmed that diabetic patients showed increased cardiac fibrosis that EndMT had occurred. Tissue curls from the paraffin-embedded tissues were used for RT-qPCR and methylation analyses. RT-qPCR quantitatively showed that EndMT occurs in the hearts of diabetics, and that EndMT in human hearts corresponded to changes in key ncRNAs. Methylation analysis showed that some of the EndMT-related ncRNAs were regulated by DNA promoter methylation, while others may be regulated through different epigenetic mechanisms. Conclusions We show that EndMT is a relevant pathological process in human hearts during DCM, and that its occurrence coincides with changes in relevant ncRNAs. We further find that interplay between DNA methylation and certain ncRNAs involved in the regulation of EndMT may contribute to the observed changes in ncRNA expression. These findings reinforce the role of EndMT in patients afflicted with DCM and underscore the complexities and importance of the interactions between different facets of epigenetic regulation. |
| first_indexed | 2024-03-11T12:43:58Z |
| format | Article |
| id | doaj.art-9cf1413b293c47ea9593f0824e641316 |
| institution | Directory Open Access Journal |
| issn | 1475-2840 |
| language | English |
| last_indexed | 2024-03-11T12:43:58Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Cardiovascular Diabetology |
| spelling | doaj.art-9cf1413b293c47ea9593f0824e6413162023-11-05T12:06:59ZengBMCCardiovascular Diabetology1475-28402023-11-0122111310.1186/s12933-023-02039-4Non-coding RNA-mediated endothelial-to-mesenchymal transition in human diabetic cardiomyopathy, potential regulation by DNA methylationEric Wang0Shali Chen1Honglin Wang2Tori Chen3Subrata Chakrabarti4Department of Pathology and Laboratory Medicine, Western UniversityDepartment of Pathology and Laboratory Medicine, Western UniversityDepartment of Pathology and Laboratory Medicine, Western UniversityDepartment of Pathology and Laboratory Medicine, Western UniversityDepartment of Pathology and Laboratory Medicine, Western UniversityAbstract Aims Diabetic cardiomyopathy (DCM) is a major complication of diabetes and a risk factor for cardiovascular disease. Endothelial dysfunction is central to DCM, and endothelial-to-mesenchymal transition (EndMT) is a key form of endothelial dysfunction in diabetes. EndMT in DCM has been well-studied in model systems and has been found to be epigenetically regulated by non-coding RNAs (ncRNAs). However, EndMT in DCM and its associated epigenetic changes need further characterization in human patients. It is also not known if ncRNAs are affected by changes in DNA methylation in DCM. This study aims to confirm in human hearts, the findings from animal and cell studies, and potentially provide novel insight into interactions between DNA methylation and ncRNAs in EndMT in DCM. Methods and results Heart tissues were collected from autopsy patients, fixed in formalin, and embedded in paraffin. Thin sections from paraffin-embedded tissues were used for histology and immunofluorescence analyses, where we confirmed that diabetic patients showed increased cardiac fibrosis that EndMT had occurred. Tissue curls from the paraffin-embedded tissues were used for RT-qPCR and methylation analyses. RT-qPCR quantitatively showed that EndMT occurs in the hearts of diabetics, and that EndMT in human hearts corresponded to changes in key ncRNAs. Methylation analysis showed that some of the EndMT-related ncRNAs were regulated by DNA promoter methylation, while others may be regulated through different epigenetic mechanisms. Conclusions We show that EndMT is a relevant pathological process in human hearts during DCM, and that its occurrence coincides with changes in relevant ncRNAs. We further find that interplay between DNA methylation and certain ncRNAs involved in the regulation of EndMT may contribute to the observed changes in ncRNA expression. These findings reinforce the role of EndMT in patients afflicted with DCM and underscore the complexities and importance of the interactions between different facets of epigenetic regulation.https://doi.org/10.1186/s12933-023-02039-4Diabetic cardiomyopathyEndothelial-to-mesenchymal transitionEpigeneticsLong non-coding RNAmicroRNAPromoter methylation |
| spellingShingle | Eric Wang Shali Chen Honglin Wang Tori Chen Subrata Chakrabarti Non-coding RNA-mediated endothelial-to-mesenchymal transition in human diabetic cardiomyopathy, potential regulation by DNA methylation Cardiovascular Diabetology Diabetic cardiomyopathy Endothelial-to-mesenchymal transition Epigenetics Long non-coding RNA microRNA Promoter methylation |
| title | Non-coding RNA-mediated endothelial-to-mesenchymal transition in human diabetic cardiomyopathy, potential regulation by DNA methylation |
| title_full | Non-coding RNA-mediated endothelial-to-mesenchymal transition in human diabetic cardiomyopathy, potential regulation by DNA methylation |
| title_fullStr | Non-coding RNA-mediated endothelial-to-mesenchymal transition in human diabetic cardiomyopathy, potential regulation by DNA methylation |
| title_full_unstemmed | Non-coding RNA-mediated endothelial-to-mesenchymal transition in human diabetic cardiomyopathy, potential regulation by DNA methylation |
| title_short | Non-coding RNA-mediated endothelial-to-mesenchymal transition in human diabetic cardiomyopathy, potential regulation by DNA methylation |
| title_sort | non coding rna mediated endothelial to mesenchymal transition in human diabetic cardiomyopathy potential regulation by dna methylation |
| topic | Diabetic cardiomyopathy Endothelial-to-mesenchymal transition Epigenetics Long non-coding RNA microRNA Promoter methylation |
| url | https://doi.org/10.1186/s12933-023-02039-4 |
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