Nkx2‐5 Is Expressed in Atherosclerotic Plaques and Attenuates Development of Atherosclerosis in Apolipoprotein E–Deficient Mice
BackgroundNK2 homeobox 5 (Nkx2‐5) is a cardiac homeobox transcription factor that is expressed in a broad range of cardiac sublineages. Embryos lacking Nkx2‐5 are nonviable attributed to growth retardation and gross abnormalities of the heart. However, the role of Nkx2‐5 in atherosclerosis remains e...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2016-12-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.116.004440 |
| _version_ | 1819205588617265152 |
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| author | Meng Du Xiaojing Wang Xin Tan Xiangrao Li Dandan Huang Kun Huang Liu Yang Fengxiao Zhang Yan Wang Dan Huang Kai Huang |
| author_facet | Meng Du Xiaojing Wang Xin Tan Xiangrao Li Dandan Huang Kun Huang Liu Yang Fengxiao Zhang Yan Wang Dan Huang Kai Huang |
| author_sort | Meng Du |
| collection | DOAJ |
| description | BackgroundNK2 homeobox 5 (Nkx2‐5) is a cardiac homeobox transcription factor that is expressed in a broad range of cardiac sublineages. Embryos lacking Nkx2‐5 are nonviable attributed to growth retardation and gross abnormalities of the heart. However, the role of Nkx2‐5 in atherosclerosis remains elusive. This study aims to elucidate the specific functions of Nkx2‐5 during atherogenesis and in established atherosclerotic plaques. Methods and ResultsTwo types of atherosclerotic lesions were created in ApoE−/− mice through 2 different dietary manipulations. Mice fed a standard chow diet were sacrificed at 20 weeks old, a time point at which mice developed early‐stage atherosclerotic lesions. The other half of mice were fed a western diet from 6 to 22 weeks old and then sacrificed. These mice demonstrated advanced atherosclerosis. No Nkx2‐5 was detected in normal arteries; however, it was abundantly present in the intima of atherosclerotic lesions and localized in macrophages and smooth muscle cells. Adenovirus gene transfer of Nkx2‐5 markedly ameliorated and stabilized the atherosclerotic plaques, and knockdown of Nkx2‐5 significantly exacerbated the disease. Molecular studies indicated that expression of specific members of matrix metalloproteinases and tissue inhibitor of metalloproteinases, which play a crucial role in the progression of atherosclerosis, were directly regulated by Nkx2‐5. Furthermore, we demonstrated that the compromised endothelial function, which was considered as a hallmark of early atherosclerosis, could be improved by Nkx2‐5 gene transfer. ConclusionsNkx2‐5 exerts antiatherogenic effects, which may partly be attributed to regulation on matrix metalloproteinases and tissue inhibitor of metalloproteinases, thus stabilizing atherosclerotic plaque; besides, it improves endothelial function by inhibiting leukocyte adhesion to the endothelium. |
| first_indexed | 2024-12-23T04:54:06Z |
| format | Article |
| id | doaj.art-a46ddbbebb85434799f6fcbbd8eb3320 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-23T04:54:06Z |
| publishDate | 2016-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-a46ddbbebb85434799f6fcbbd8eb33202022-12-21T17:59:23ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802016-12-0151210.1161/JAHA.116.004440Nkx2‐5 Is Expressed in Atherosclerotic Plaques and Attenuates Development of Atherosclerosis in Apolipoprotein E–Deficient MiceMeng Du0Xiaojing Wang1Xin Tan2Xiangrao Li3Dandan Huang4Kun Huang5Liu Yang6Fengxiao Zhang7Yan Wang8Dan Huang9Kai Huang10Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaBackgroundNK2 homeobox 5 (Nkx2‐5) is a cardiac homeobox transcription factor that is expressed in a broad range of cardiac sublineages. Embryos lacking Nkx2‐5 are nonviable attributed to growth retardation and gross abnormalities of the heart. However, the role of Nkx2‐5 in atherosclerosis remains elusive. This study aims to elucidate the specific functions of Nkx2‐5 during atherogenesis and in established atherosclerotic plaques. Methods and ResultsTwo types of atherosclerotic lesions were created in ApoE−/− mice through 2 different dietary manipulations. Mice fed a standard chow diet were sacrificed at 20 weeks old, a time point at which mice developed early‐stage atherosclerotic lesions. The other half of mice were fed a western diet from 6 to 22 weeks old and then sacrificed. These mice demonstrated advanced atherosclerosis. No Nkx2‐5 was detected in normal arteries; however, it was abundantly present in the intima of atherosclerotic lesions and localized in macrophages and smooth muscle cells. Adenovirus gene transfer of Nkx2‐5 markedly ameliorated and stabilized the atherosclerotic plaques, and knockdown of Nkx2‐5 significantly exacerbated the disease. Molecular studies indicated that expression of specific members of matrix metalloproteinases and tissue inhibitor of metalloproteinases, which play a crucial role in the progression of atherosclerosis, were directly regulated by Nkx2‐5. Furthermore, we demonstrated that the compromised endothelial function, which was considered as a hallmark of early atherosclerosis, could be improved by Nkx2‐5 gene transfer. ConclusionsNkx2‐5 exerts antiatherogenic effects, which may partly be attributed to regulation on matrix metalloproteinases and tissue inhibitor of metalloproteinases, thus stabilizing atherosclerotic plaque; besides, it improves endothelial function by inhibiting leukocyte adhesion to the endothelium.https://www.ahajournals.org/doi/10.1161/JAHA.116.004440atherosclerosismatrix metalloproteinasesNK2 homeobox 5plaque stability |
| spellingShingle | Meng Du Xiaojing Wang Xin Tan Xiangrao Li Dandan Huang Kun Huang Liu Yang Fengxiao Zhang Yan Wang Dan Huang Kai Huang Nkx2‐5 Is Expressed in Atherosclerotic Plaques and Attenuates Development of Atherosclerosis in Apolipoprotein E–Deficient Mice Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease atherosclerosis matrix metalloproteinases NK2 homeobox 5 plaque stability |
| title | Nkx2‐5 Is Expressed in Atherosclerotic Plaques and Attenuates Development of Atherosclerosis in Apolipoprotein E–Deficient Mice |
| title_full | Nkx2‐5 Is Expressed in Atherosclerotic Plaques and Attenuates Development of Atherosclerosis in Apolipoprotein E–Deficient Mice |
| title_fullStr | Nkx2‐5 Is Expressed in Atherosclerotic Plaques and Attenuates Development of Atherosclerosis in Apolipoprotein E–Deficient Mice |
| title_full_unstemmed | Nkx2‐5 Is Expressed in Atherosclerotic Plaques and Attenuates Development of Atherosclerosis in Apolipoprotein E–Deficient Mice |
| title_short | Nkx2‐5 Is Expressed in Atherosclerotic Plaques and Attenuates Development of Atherosclerosis in Apolipoprotein E–Deficient Mice |
| title_sort | nkx2 5 is expressed in atherosclerotic plaques and attenuates development of atherosclerosis in apolipoprotein e deficient mice |
| topic | atherosclerosis matrix metalloproteinases NK2 homeobox 5 plaque stability |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.116.004440 |
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