Nuclear membrane ruptures underlie the vascular pathology in a mouse model of Hutchinson-Gilford progeria syndrome
The mutant nuclear lamin protein (progerin) produced in Hutchinson-Gilford progeria syndrome (HGPS) results in loss of arterial smooth muscle cells (SMCs), but the mechanism has been unclear. We found that progerin induces repetitive nuclear membrane (NM) ruptures, DNA damage, and cell death in cult...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-08-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.151515 |
| _version_ | 1811329159491747840 |
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| author | Paul H. Kim Natalie Y. Chen Patrick J. Heizer Yiping Tu Thomas A. Weston Jared L.-C. Fong Navjot Kaur Gill Amy C. Rowat Stephen G. Young Loren G. Fong |
| author_facet | Paul H. Kim Natalie Y. Chen Patrick J. Heizer Yiping Tu Thomas A. Weston Jared L.-C. Fong Navjot Kaur Gill Amy C. Rowat Stephen G. Young Loren G. Fong |
| author_sort | Paul H. Kim |
| collection | DOAJ |
| description | The mutant nuclear lamin protein (progerin) produced in Hutchinson-Gilford progeria syndrome (HGPS) results in loss of arterial smooth muscle cells (SMCs), but the mechanism has been unclear. We found that progerin induces repetitive nuclear membrane (NM) ruptures, DNA damage, and cell death in cultured SMCs. Reducing lamin B1 expression and exposing cells to mechanical stress — to mirror conditions in the aorta — triggered more frequent NM ruptures. Increasing lamin B1 protein levels had the opposite effect, reducing NM ruptures and improving cell survival. Remarkably, raising lamin B1 levels increased nuclear compliance in cells and was able to offset the increased nuclear stiffness caused by progerin. In mice, lamin B1 expression in aortic SMCs is normally very low, and in mice with a targeted HGPS mutation (LmnaG609G), levels of lamin B1 decrease further with age while progerin levels increase. Those observations suggest that NM ruptures might occur in aortic SMCs in vivo. Indeed, studies in LmnaG609G mice identified NM ruptures in aortic SMCs, along with ultrastructural abnormalities in the cell nucleus that preceded SMC loss. Our studies identify NM ruptures in SMCs as likely causes of vascular pathology in HGPS. |
| first_indexed | 2024-04-13T15:38:53Z |
| format | Article |
| id | doaj.art-782e92b7c80f4e82b3a9551cf8e5b14f |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-13T15:38:53Z |
| publishDate | 2021-08-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-782e92b7c80f4e82b3a9551cf8e5b14f2022-12-22T02:41:12ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-08-01616Nuclear membrane ruptures underlie the vascular pathology in a mouse model of Hutchinson-Gilford progeria syndromePaul H. KimNatalie Y. ChenPatrick J. HeizerYiping TuThomas A. WestonJared L.-C. FongNavjot Kaur GillAmy C. RowatStephen G. YoungLoren G. FongThe mutant nuclear lamin protein (progerin) produced in Hutchinson-Gilford progeria syndrome (HGPS) results in loss of arterial smooth muscle cells (SMCs), but the mechanism has been unclear. We found that progerin induces repetitive nuclear membrane (NM) ruptures, DNA damage, and cell death in cultured SMCs. Reducing lamin B1 expression and exposing cells to mechanical stress — to mirror conditions in the aorta — triggered more frequent NM ruptures. Increasing lamin B1 protein levels had the opposite effect, reducing NM ruptures and improving cell survival. Remarkably, raising lamin B1 levels increased nuclear compliance in cells and was able to offset the increased nuclear stiffness caused by progerin. In mice, lamin B1 expression in aortic SMCs is normally very low, and in mice with a targeted HGPS mutation (LmnaG609G), levels of lamin B1 decrease further with age while progerin levels increase. Those observations suggest that NM ruptures might occur in aortic SMCs in vivo. Indeed, studies in LmnaG609G mice identified NM ruptures in aortic SMCs, along with ultrastructural abnormalities in the cell nucleus that preceded SMC loss. Our studies identify NM ruptures in SMCs as likely causes of vascular pathology in HGPS.https://doi.org/10.1172/jci.insight.151515Vascular biology |
| spellingShingle | Paul H. Kim Natalie Y. Chen Patrick J. Heizer Yiping Tu Thomas A. Weston Jared L.-C. Fong Navjot Kaur Gill Amy C. Rowat Stephen G. Young Loren G. Fong Nuclear membrane ruptures underlie the vascular pathology in a mouse model of Hutchinson-Gilford progeria syndrome JCI Insight Vascular biology |
| title | Nuclear membrane ruptures underlie the vascular pathology in a mouse model of Hutchinson-Gilford progeria syndrome |
| title_full | Nuclear membrane ruptures underlie the vascular pathology in a mouse model of Hutchinson-Gilford progeria syndrome |
| title_fullStr | Nuclear membrane ruptures underlie the vascular pathology in a mouse model of Hutchinson-Gilford progeria syndrome |
| title_full_unstemmed | Nuclear membrane ruptures underlie the vascular pathology in a mouse model of Hutchinson-Gilford progeria syndrome |
| title_short | Nuclear membrane ruptures underlie the vascular pathology in a mouse model of Hutchinson-Gilford progeria syndrome |
| title_sort | nuclear membrane ruptures underlie the vascular pathology in a mouse model of hutchinson gilford progeria syndrome |
| topic | Vascular biology |
| url | https://doi.org/10.1172/jci.insight.151515 |
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