Seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve diseaseResearch in context
Background: Ascending aortic aneurysms constitute an important hazard for individuals with a bicuspid aortic valve (BAV). However, the processes that degrade the aortic wall in BAV disease remain poorly understood. Methods: We undertook in situ analysis of ascending aortas from 68 patients, seeking...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-05-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396419302993 |
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doaj-f66069968b97408188a0a4f7d3cec4ba |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Brittany Balint Hao Yin Zengxuan Nong John-Michael Arpino Caroline O'Neil Stephanie R. Rogers Varinder K. Randhawa Stephanie A. Fox Jacqueline Chevalier Jason J. Lee Michael W.A. Chu J. Geoffrey Pickering |
| spellingShingle |
Brittany Balint Hao Yin Zengxuan Nong John-Michael Arpino Caroline O'Neil Stephanie R. Rogers Varinder K. Randhawa Stephanie A. Fox Jacqueline Chevalier Jason J. Lee Michael W.A. Chu J. Geoffrey Pickering Seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve diseaseResearch in context EBioMedicine |
| author_facet |
Brittany Balint Hao Yin Zengxuan Nong John-Michael Arpino Caroline O'Neil Stephanie R. Rogers Varinder K. Randhawa Stephanie A. Fox Jacqueline Chevalier Jason J. Lee Michael W.A. Chu J. Geoffrey Pickering |
| author_sort |
Brittany Balint |
| title |
Seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve diseaseResearch in context |
| title_short |
Seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve diseaseResearch in context |
| title_full |
Seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve diseaseResearch in context |
| title_fullStr |
Seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve diseaseResearch in context |
| title_full_unstemmed |
Seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve diseaseResearch in context |
| title_sort |
seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve diseaseresearch in context |
| publisher |
Elsevier |
| series |
EBioMedicine |
| issn |
2352-3964 |
| publishDate |
2019-05-01 |
| description |
Background: Ascending aortic aneurysms constitute an important hazard for individuals with a bicuspid aortic valve (BAV). However, the processes that degrade the aortic wall in BAV disease remain poorly understood. Methods: We undertook in situ analysis of ascending aortas from 68 patients, seeking potentially damaging cellular senescence cascades. Aortas were assessed for senescence-associated-ß-galactosidase activity, p16Ink4a and p21 expression, and double-strand DNA breaks. The senescence-associated secretory phenotype (SASP) of cultured-aged BAV aortic smooth muscle cells (SMCs) was evaluated by transcript profiling and consequences probed by combined immunofluorescence and circular polarization microscopy. The contribution of p38 MAPK signaling was assessed by immunostaining and blocking strategies. Findings: We uncovered SMCs at varying depths of cellular senescence within BAV- and tricuspid aortic valve (TAV)-associated aortic aneurysms. Senescent SMCs were also abundant in non-aneurysmal BAV aortas but not in non-aneurysmal TAV aortas. Multivariable analysis revealed that BAV disease independently associated with SMC senescence. Furthermre, SMC senescence was heightened at the convexity of aortas associated with right-left coronary cusp fusion. Aged BAV SMCs had a pronounced collagenolytic SASP. Moreover, senescent SMCs in the aortic wall were enriched with surface-localized MMP1 and surrounded by weakly birefringent collagen fibrils. The senescent-collagenolytic SMC phenotype depended on p38 MAPK signaling, which was chronically activated in BAV aortas. Interpretation: We have identified a cellular senescence-collagen destruction axis in at-risk ascending aortas. This novel “seno-destructive” SMC phenotype could open new opportunities for managing BAV aortopathy. Fund: Canadian Institutes of Health Research, Lawson Health Research Institute, Heart and Stroke Foundation of Ontario/Barnett-Ivey Chair. Keywords: Bicuspid aortic valve, Aortic aneurysm, Smooth muscle cells, Cellular senescence, Collagenase |
| url |
http://www.sciencedirect.com/science/article/pii/S2352396419302993 |
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doaj-f66069968b97408188a0a4f7d3cec4ba2020-11-25T01:52:43ZengElsevierEBioMedicine2352-39642019-05-01435466Seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve diseaseResearch in contextBrittany Balint0Hao Yin1Zengxuan Nong2John-Michael Arpino3Caroline O'Neil4Stephanie R. Rogers5Varinder K. Randhawa6Stephanie A. Fox7Jacqueline Chevalier8Jason J. Lee9Michael W.A. Chu10J. Geoffrey Pickering11Robarts Research Institute, The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5B7, Canada; Department of Medical Biophysics, The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5C1, CanadaRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5B7, CanadaRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5B7, CanadaRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5B7, Canada; Department of Medical Biophysics, The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5C1, CanadaRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5B7, CanadaRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5B7, CanadaDepartments of Medicine (Cardiology), The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5C1, CanadaDepartment of Surgery, The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5C1, Canada; London Health Sciences Centre, 339 Windermere Rd., London, ON N6A 5A5, CanadaRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5B7, Canada; Department of Medical Biophysics, The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5C1, CanadaRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5B7, Canada; Department of Medical Biophysics, The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5C1, CanadaDepartment of Surgery, The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5C1, Canada; London Health Sciences Centre, 339 Windermere Rd., London, ON N6A 5A5, CanadaRobarts Research Institute, The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5B7, Canada; Department of Medical Biophysics, The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5C1, Canada; Departments of Medicine (Cardiology), The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5C1, Canada; London Health Sciences Centre, 339 Windermere Rd., London, ON N6A 5A5, Canada; Department of Biochemistry, The University of Western Ontario, 1151 Richmond St. N., London, ON N6A 5C1, Canada; Corresponding author at: London Health Sciences Centre, 339 Windermere Rd., London, ON N6A 5A5, Canada.Background: Ascending aortic aneurysms constitute an important hazard for individuals with a bicuspid aortic valve (BAV). However, the processes that degrade the aortic wall in BAV disease remain poorly understood. Methods: We undertook in situ analysis of ascending aortas from 68 patients, seeking potentially damaging cellular senescence cascades. Aortas were assessed for senescence-associated-ß-galactosidase activity, p16Ink4a and p21 expression, and double-strand DNA breaks. The senescence-associated secretory phenotype (SASP) of cultured-aged BAV aortic smooth muscle cells (SMCs) was evaluated by transcript profiling and consequences probed by combined immunofluorescence and circular polarization microscopy. The contribution of p38 MAPK signaling was assessed by immunostaining and blocking strategies. Findings: We uncovered SMCs at varying depths of cellular senescence within BAV- and tricuspid aortic valve (TAV)-associated aortic aneurysms. Senescent SMCs were also abundant in non-aneurysmal BAV aortas but not in non-aneurysmal TAV aortas. Multivariable analysis revealed that BAV disease independently associated with SMC senescence. Furthermre, SMC senescence was heightened at the convexity of aortas associated with right-left coronary cusp fusion. Aged BAV SMCs had a pronounced collagenolytic SASP. Moreover, senescent SMCs in the aortic wall were enriched with surface-localized MMP1 and surrounded by weakly birefringent collagen fibrils. The senescent-collagenolytic SMC phenotype depended on p38 MAPK signaling, which was chronically activated in BAV aortas. Interpretation: We have identified a cellular senescence-collagen destruction axis in at-risk ascending aortas. This novel “seno-destructive” SMC phenotype could open new opportunities for managing BAV aortopathy. Fund: Canadian Institutes of Health Research, Lawson Health Research Institute, Heart and Stroke Foundation of Ontario/Barnett-Ivey Chair. Keywords: Bicuspid aortic valve, Aortic aneurysm, Smooth muscle cells, Cellular senescence, Collagenasehttp://www.sciencedirect.com/science/article/pii/S2352396419302993 |