miR-632 Induces DNAJB6 Inhibition Stimulating Endothelial-to-Mesenchymal Transition and Fibrosis in Marfan Syndrome Aortopathy
Marfan syndrome (MFS) is a connective tissue disorder caused by <i>FBN1</i> gene mutations leading to TGF-β signaling hyperactivation, vascular wall weakness, and thoracic aortic aneurysms (TAAs). The pathogenetic mechanisms are not completely understood and patients undergo early vascul...
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MDPI AG
2023-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/20/15133 |
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| author | Sonia Terriaca Maria Giovanna Scioli Calogera Pisano Giovanni Ruvolo Amedeo Ferlosio Augusto Orlandi |
| author_facet | Sonia Terriaca Maria Giovanna Scioli Calogera Pisano Giovanni Ruvolo Amedeo Ferlosio Augusto Orlandi |
| author_sort | Sonia Terriaca |
| collection | DOAJ |
| description | Marfan syndrome (MFS) is a connective tissue disorder caused by <i>FBN1</i> gene mutations leading to TGF-β signaling hyperactivation, vascular wall weakness, and thoracic aortic aneurysms (TAAs). The pathogenetic mechanisms are not completely understood and patients undergo early vascular surgery to prevent TAA ruptures. We previously reported miR-632 upregulation in MFS TAA tissues compared with non-genetic TAA tissues. DNAJB6 is a gene target of miR-632 in cancer and plays a critical role in blocking epithelial-to-mesenchymal transition by inhibiting the Wnt/β catenin pathway. TGF-β signaling also activates Wnt/β catenin signaling and induces endothelial-to-mesenchymal transition (End-Mt) and fibrosis. We documented that miR-632 upregulation correlated with DNAJB6 expression in both the endothelium and the tunica media of MFS TAA (<i>p</i> < 0.01). Wnt/β catenin signaling, End-Mt, and fibrosis markers were also upregulated in MFS TAA tissues (<i>p</i> < 0.05, <i>p</i> < 0.01 and <i>p</i> < 0.001). Moreover, miR-632 overexpression inhibited <i>DNAJB6</i>, inducing Wnt/β catenin signaling, as well as End-Mt and fibrosis exacerbation (<i>p</i> < 0.05 and <i>p</i> < 0.01). TGF-β1 treatment also determined miR-632 upregulation (<i>p</i> < 0.01 and <i>p</i> < 0.001), with the consequent activation of the aforementioned processes. Our study provides new insights about the pathogenetic mechanisms in MFS aortopathy. Moreover, the high disease specificity of miR-632 and DNAJB6 suggests new potential prognostic factors and/or therapeutic targets in the progression of MFS aortopathy. |
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| language | English |
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| publishDate | 2023-10-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d2c40fd701ef4351ab20d3e6f90adf972023-11-19T16:42:08ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-10-0124201513310.3390/ijms242015133miR-632 Induces DNAJB6 Inhibition Stimulating Endothelial-to-Mesenchymal Transition and Fibrosis in Marfan Syndrome AortopathySonia Terriaca0Maria Giovanna Scioli1Calogera Pisano2Giovanni Ruvolo3Amedeo Ferlosio4Augusto Orlandi5Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University, 00133 Rome, ItalyAnatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University, 00133 Rome, ItalyCardiac Surgery, Department of Surgical Sciences, Tor Vergata University, 00133 Rome, ItalyCardiac Surgery, Department of Surgical Sciences, Tor Vergata University, 00133 Rome, ItalyAnatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University, 00133 Rome, ItalyAnatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University, 00133 Rome, ItalyMarfan syndrome (MFS) is a connective tissue disorder caused by <i>FBN1</i> gene mutations leading to TGF-β signaling hyperactivation, vascular wall weakness, and thoracic aortic aneurysms (TAAs). The pathogenetic mechanisms are not completely understood and patients undergo early vascular surgery to prevent TAA ruptures. We previously reported miR-632 upregulation in MFS TAA tissues compared with non-genetic TAA tissues. DNAJB6 is a gene target of miR-632 in cancer and plays a critical role in blocking epithelial-to-mesenchymal transition by inhibiting the Wnt/β catenin pathway. TGF-β signaling also activates Wnt/β catenin signaling and induces endothelial-to-mesenchymal transition (End-Mt) and fibrosis. We documented that miR-632 upregulation correlated with DNAJB6 expression in both the endothelium and the tunica media of MFS TAA (<i>p</i> < 0.01). Wnt/β catenin signaling, End-Mt, and fibrosis markers were also upregulated in MFS TAA tissues (<i>p</i> < 0.05, <i>p</i> < 0.01 and <i>p</i> < 0.001). Moreover, miR-632 overexpression inhibited <i>DNAJB6</i>, inducing Wnt/β catenin signaling, as well as End-Mt and fibrosis exacerbation (<i>p</i> < 0.05 and <i>p</i> < 0.01). TGF-β1 treatment also determined miR-632 upregulation (<i>p</i> < 0.01 and <i>p</i> < 0.001), with the consequent activation of the aforementioned processes. Our study provides new insights about the pathogenetic mechanisms in MFS aortopathy. Moreover, the high disease specificity of miR-632 and DNAJB6 suggests new potential prognostic factors and/or therapeutic targets in the progression of MFS aortopathy.https://www.mdpi.com/1422-0067/24/20/15133Marfan syndromethoracic aortic aneurysmsaortic wall degenerationendothelial-to-mesenchymal transitionfibrosisTGF-β1 |
| spellingShingle | Sonia Terriaca Maria Giovanna Scioli Calogera Pisano Giovanni Ruvolo Amedeo Ferlosio Augusto Orlandi miR-632 Induces DNAJB6 Inhibition Stimulating Endothelial-to-Mesenchymal Transition and Fibrosis in Marfan Syndrome Aortopathy International Journal of Molecular Sciences Marfan syndrome thoracic aortic aneurysms aortic wall degeneration endothelial-to-mesenchymal transition fibrosis TGF-β1 |
| title | miR-632 Induces DNAJB6 Inhibition Stimulating Endothelial-to-Mesenchymal Transition and Fibrosis in Marfan Syndrome Aortopathy |
| title_full | miR-632 Induces DNAJB6 Inhibition Stimulating Endothelial-to-Mesenchymal Transition and Fibrosis in Marfan Syndrome Aortopathy |
| title_fullStr | miR-632 Induces DNAJB6 Inhibition Stimulating Endothelial-to-Mesenchymal Transition and Fibrosis in Marfan Syndrome Aortopathy |
| title_full_unstemmed | miR-632 Induces DNAJB6 Inhibition Stimulating Endothelial-to-Mesenchymal Transition and Fibrosis in Marfan Syndrome Aortopathy |
| title_short | miR-632 Induces DNAJB6 Inhibition Stimulating Endothelial-to-Mesenchymal Transition and Fibrosis in Marfan Syndrome Aortopathy |
| title_sort | mir 632 induces dnajb6 inhibition stimulating endothelial to mesenchymal transition and fibrosis in marfan syndrome aortopathy |
| topic | Marfan syndrome thoracic aortic aneurysms aortic wall degeneration endothelial-to-mesenchymal transition fibrosis TGF-β1 |
| url | https://www.mdpi.com/1422-0067/24/20/15133 |
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