Reciprocal regulation of endothelial–mesenchymal transition by MAPK7 and EZH2 in intimal hyperplasia and coronary artery disease
Abstract Endothelial–mesenchymal transition (EndMT) is a form of endothelial dysfunction wherein endothelial cells acquire a mesenchymal phenotype and lose endothelial functions, which contributes to the pathogenesis of intimal hyperplasia and atherosclerosis. The mitogen activated protein kinase 7...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-09-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-97127-4 |
| _version_ | 1818683792012869632 |
|---|---|
| author | Byambasuren Vanchin Marloes Sol Rutger A. F. Gjaltema Marja Brinker Bianca Kiers Alexandre C. Pereira Martin C. Harmsen Jan-Renier A. J. Moonen Guido Krenning |
| author_facet | Byambasuren Vanchin Marloes Sol Rutger A. F. Gjaltema Marja Brinker Bianca Kiers Alexandre C. Pereira Martin C. Harmsen Jan-Renier A. J. Moonen Guido Krenning |
| author_sort | Byambasuren Vanchin |
| collection | DOAJ |
| description | Abstract Endothelial–mesenchymal transition (EndMT) is a form of endothelial dysfunction wherein endothelial cells acquire a mesenchymal phenotype and lose endothelial functions, which contributes to the pathogenesis of intimal hyperplasia and atherosclerosis. The mitogen activated protein kinase 7 (MAPK7) inhibits EndMT and decreases the expression of the histone methyltransferase Enhancer-of-Zeste homologue 2 (EZH2), thereby maintaining endothelial quiescence. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 that methylates lysine 27 on histone 3 (H3K27me3). It is elusive how the crosstalk between MAPK7 and EZH2 is regulated in the endothelium and if the balance between MAPK7 and EZH2 is disturbed in vascular disease. In human coronary artery disease, we assessed the expression levels of MAPK7 and EZH2 and found that with increasing intima/media thickness ratio, MAPK7 expression decreased, whereas EZH2 expression increased. In vitro, MAPK7 activation decreased EZH2 expression, whereas endothelial cells deficient of EZH2 had increased MAPK7 activity. MAPK7 activation results in increased expression of microRNA (miR)-101, a repressor of EZH2. This loss of EZH2 in turn results in the increased expression of the miR-200 family, culminating in decreased expression of the dual-specificity phosphatases 1 and 6 who may repress MAPK7 activity. Transfection of endothelial cells with miR-200 family members decreased the endothelial sensitivity to TGFβ1-induced EndMT. In endothelial cells there is reciprocity between MAPK7 signaling and EZH2 expression and disturbances in this reciprocal signaling associate with the induction of EndMT and severity of human coronary artery disease. |
| first_indexed | 2024-12-17T10:40:22Z |
| format | Article |
| id | doaj.art-cef5017f27294af6a8fb7b89df615909 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-17T10:40:22Z |
| publishDate | 2021-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-cef5017f27294af6a8fb7b89df6159092022-12-21T21:52:16ZengNature PortfolioScientific Reports2045-23222021-09-0111111610.1038/s41598-021-97127-4Reciprocal regulation of endothelial–mesenchymal transition by MAPK7 and EZH2 in intimal hyperplasia and coronary artery diseaseByambasuren Vanchin0Marloes Sol1Rutger A. F. Gjaltema2Marja Brinker3Bianca Kiers4Alexandre C. Pereira5Martin C. Harmsen6Jan-Renier A. J. Moonen7Guido Krenning8Laboratory for Cardiovascular Regenerative Medicine, Department of Pathology and Medical Biology, University Medical Center Groningen, University of GroningenLaboratory for Cardiovascular Regenerative Medicine, Department of Pathology and Medical Biology, University Medical Center Groningen, University of GroningenLaboratory for Cardiovascular Regenerative Medicine, Department of Pathology and Medical Biology, University Medical Center Groningen, University of GroningenLaboratory for Cardiovascular Regenerative Medicine, Department of Pathology and Medical Biology, University Medical Center Groningen, University of GroningenLaboratory of Genetics and Molecular Cardiology (LIM13), Heart Institute (InCor), University of São PauloLaboratory of Genetics and Molecular Cardiology (LIM13), Heart Institute (InCor), University of São PauloLaboratory for Cardiovascular Regenerative Medicine, Department of Pathology and Medical Biology, University Medical Center Groningen, University of GroningenLaboratory for Cardiovascular Regenerative Medicine, Department of Pathology and Medical Biology, University Medical Center Groningen, University of GroningenLaboratory for Cardiovascular Regenerative Medicine, Department of Pathology and Medical Biology, University Medical Center Groningen, University of GroningenAbstract Endothelial–mesenchymal transition (EndMT) is a form of endothelial dysfunction wherein endothelial cells acquire a mesenchymal phenotype and lose endothelial functions, which contributes to the pathogenesis of intimal hyperplasia and atherosclerosis. The mitogen activated protein kinase 7 (MAPK7) inhibits EndMT and decreases the expression of the histone methyltransferase Enhancer-of-Zeste homologue 2 (EZH2), thereby maintaining endothelial quiescence. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 that methylates lysine 27 on histone 3 (H3K27me3). It is elusive how the crosstalk between MAPK7 and EZH2 is regulated in the endothelium and if the balance between MAPK7 and EZH2 is disturbed in vascular disease. In human coronary artery disease, we assessed the expression levels of MAPK7 and EZH2 and found that with increasing intima/media thickness ratio, MAPK7 expression decreased, whereas EZH2 expression increased. In vitro, MAPK7 activation decreased EZH2 expression, whereas endothelial cells deficient of EZH2 had increased MAPK7 activity. MAPK7 activation results in increased expression of microRNA (miR)-101, a repressor of EZH2. This loss of EZH2 in turn results in the increased expression of the miR-200 family, culminating in decreased expression of the dual-specificity phosphatases 1 and 6 who may repress MAPK7 activity. Transfection of endothelial cells with miR-200 family members decreased the endothelial sensitivity to TGFβ1-induced EndMT. In endothelial cells there is reciprocity between MAPK7 signaling and EZH2 expression and disturbances in this reciprocal signaling associate with the induction of EndMT and severity of human coronary artery disease.https://doi.org/10.1038/s41598-021-97127-4 |
| spellingShingle | Byambasuren Vanchin Marloes Sol Rutger A. F. Gjaltema Marja Brinker Bianca Kiers Alexandre C. Pereira Martin C. Harmsen Jan-Renier A. J. Moonen Guido Krenning Reciprocal regulation of endothelial–mesenchymal transition by MAPK7 and EZH2 in intimal hyperplasia and coronary artery disease Scientific Reports |
| title | Reciprocal regulation of endothelial–mesenchymal transition by MAPK7 and EZH2 in intimal hyperplasia and coronary artery disease |
| title_full | Reciprocal regulation of endothelial–mesenchymal transition by MAPK7 and EZH2 in intimal hyperplasia and coronary artery disease |
| title_fullStr | Reciprocal regulation of endothelial–mesenchymal transition by MAPK7 and EZH2 in intimal hyperplasia and coronary artery disease |
| title_full_unstemmed | Reciprocal regulation of endothelial–mesenchymal transition by MAPK7 and EZH2 in intimal hyperplasia and coronary artery disease |
| title_short | Reciprocal regulation of endothelial–mesenchymal transition by MAPK7 and EZH2 in intimal hyperplasia and coronary artery disease |
| title_sort | reciprocal regulation of endothelial mesenchymal transition by mapk7 and ezh2 in intimal hyperplasia and coronary artery disease |
| url | https://doi.org/10.1038/s41598-021-97127-4 |
| work_keys_str_mv | AT byambasurenvanchin reciprocalregulationofendothelialmesenchymaltransitionbymapk7andezh2inintimalhyperplasiaandcoronaryarterydisease AT marloessol reciprocalregulationofendothelialmesenchymaltransitionbymapk7andezh2inintimalhyperplasiaandcoronaryarterydisease AT rutgerafgjaltema reciprocalregulationofendothelialmesenchymaltransitionbymapk7andezh2inintimalhyperplasiaandcoronaryarterydisease AT marjabrinker reciprocalregulationofendothelialmesenchymaltransitionbymapk7andezh2inintimalhyperplasiaandcoronaryarterydisease AT biancakiers reciprocalregulationofendothelialmesenchymaltransitionbymapk7andezh2inintimalhyperplasiaandcoronaryarterydisease AT alexandrecpereira reciprocalregulationofendothelialmesenchymaltransitionbymapk7andezh2inintimalhyperplasiaandcoronaryarterydisease AT martincharmsen reciprocalregulationofendothelialmesenchymaltransitionbymapk7andezh2inintimalhyperplasiaandcoronaryarterydisease AT janrenierajmoonen reciprocalregulationofendothelialmesenchymaltransitionbymapk7andezh2inintimalhyperplasiaandcoronaryarterydisease AT guidokrenning reciprocalregulationofendothelialmesenchymaltransitionbymapk7andezh2inintimalhyperplasiaandcoronaryarterydisease |