Multi-Omics of Familial Thoracic Aortic Aneurysm and Dissection: Calcium Transport Impairment Predisposes Aortas to Dissection
Several genetic defects, including a mutation in myosin heavy chain 11 (<i>Myh11</i>), are reported to cause familial thoracic aortic aneurysm and dissection (FTAAD). We recently showed that mice lacking K1256 of Myh11 developed aortic dissection when stimulated with angiotensin II, desp...
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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/1422-0067/24/20/15213 |
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| author | Shota Tomida Tamaki Ishima Daigo Sawaki Yasushi Imai Ryozo Nagai Kenichi Aizawa |
| author_facet | Shota Tomida Tamaki Ishima Daigo Sawaki Yasushi Imai Ryozo Nagai Kenichi Aizawa |
| author_sort | Shota Tomida |
| collection | DOAJ |
| description | Several genetic defects, including a mutation in myosin heavy chain 11 (<i>Myh11</i>), are reported to cause familial thoracic aortic aneurysm and dissection (FTAAD). We recently showed that mice lacking K1256 of Myh11 developed aortic dissection when stimulated with angiotensin II, despite the absence of major pathological phenotypic abnormalities prior to stimulation. In this study, we used a comprehensive, data-driven, unbiased, multi-omics approach to find underlying changes in transcription and metabolism that predispose the aorta to dissection in mice harboring the Myh11 K1256del mutation. Pathway analysis of transcriptomes showed that genes involved in membrane transport were downregulated in homozygous mutant (<i>Myh11</i><sup>ΔK/ΔK</sup>) aortas. Furthermore, expanding the analysis with metabolomics showed that two mechanisms that raise the cytosolic Ca<sup>2+</sup> concentration—multiple calcium channel expression and ADP–ribose synthesis—were attenuated in <i>Myh11</i><sup>ΔK/ΔK</sup> aortas. We suggest that the impairment of the Ca<sup>2+</sup> influx attenuates aortic contraction and that suboptimal contraction predisposes the aorta to dissection. |
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| issn | 1661-6596 1422-0067 |
| language | English |
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| spelling | doaj.art-a36305766b2e4a37a9c43799b83b26912023-11-19T16:43:24ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-10-0124201521310.3390/ijms242015213Multi-Omics of Familial Thoracic Aortic Aneurysm and Dissection: Calcium Transport Impairment Predisposes Aortas to DissectionShota Tomida0Tamaki Ishima1Daigo Sawaki2Yasushi Imai3Ryozo Nagai4Kenichi Aizawa5Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke 329-0498, Tochigi, JapanDivision of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke 329-0498, Tochigi, JapanDivision of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke 329-0498, Tochigi, JapanDivision of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke 329-0498, Tochigi, JapanJichi Medical University, Shimotsuke 329-0498, Tochigi, JapanDivision of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke 329-0498, Tochigi, JapanSeveral genetic defects, including a mutation in myosin heavy chain 11 (<i>Myh11</i>), are reported to cause familial thoracic aortic aneurysm and dissection (FTAAD). We recently showed that mice lacking K1256 of Myh11 developed aortic dissection when stimulated with angiotensin II, despite the absence of major pathological phenotypic abnormalities prior to stimulation. In this study, we used a comprehensive, data-driven, unbiased, multi-omics approach to find underlying changes in transcription and metabolism that predispose the aorta to dissection in mice harboring the Myh11 K1256del mutation. Pathway analysis of transcriptomes showed that genes involved in membrane transport were downregulated in homozygous mutant (<i>Myh11</i><sup>ΔK/ΔK</sup>) aortas. Furthermore, expanding the analysis with metabolomics showed that two mechanisms that raise the cytosolic Ca<sup>2+</sup> concentration—multiple calcium channel expression and ADP–ribose synthesis—were attenuated in <i>Myh11</i><sup>ΔK/ΔK</sup> aortas. We suggest that the impairment of the Ca<sup>2+</sup> influx attenuates aortic contraction and that suboptimal contraction predisposes the aorta to dissection.https://www.mdpi.com/1422-0067/24/20/15213multi-omicsfamilial thoracic aortic aneurysm and dissectioncalcium transport |
| spellingShingle | Shota Tomida Tamaki Ishima Daigo Sawaki Yasushi Imai Ryozo Nagai Kenichi Aizawa Multi-Omics of Familial Thoracic Aortic Aneurysm and Dissection: Calcium Transport Impairment Predisposes Aortas to Dissection International Journal of Molecular Sciences multi-omics familial thoracic aortic aneurysm and dissection calcium transport |
| title | Multi-Omics of Familial Thoracic Aortic Aneurysm and Dissection: Calcium Transport Impairment Predisposes Aortas to Dissection |
| title_full | Multi-Omics of Familial Thoracic Aortic Aneurysm and Dissection: Calcium Transport Impairment Predisposes Aortas to Dissection |
| title_fullStr | Multi-Omics of Familial Thoracic Aortic Aneurysm and Dissection: Calcium Transport Impairment Predisposes Aortas to Dissection |
| title_full_unstemmed | Multi-Omics of Familial Thoracic Aortic Aneurysm and Dissection: Calcium Transport Impairment Predisposes Aortas to Dissection |
| title_short | Multi-Omics of Familial Thoracic Aortic Aneurysm and Dissection: Calcium Transport Impairment Predisposes Aortas to Dissection |
| title_sort | multi omics of familial thoracic aortic aneurysm and dissection calcium transport impairment predisposes aortas to dissection |
| topic | multi-omics familial thoracic aortic aneurysm and dissection calcium transport |
| url | https://www.mdpi.com/1422-0067/24/20/15213 |
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