Inflammatory Role of Milk Fat Globule–Epidermal Growth Factor VIII in Age‐Associated Arterial Remodeling
Background Age‐associated aortic remodeling includes a marked increase in intimal medial thickness (IMT), associated with signs of inflammation. Although aortic wall milk fat globule–epidermal growth factor VIII (MFG‐E8) increases with age, and is associated with aortic inflammation, it is not known...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-09-01
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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.121.022574 |
| _version_ | 1811261005555040256 |
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| author | Leng Ni Lijuan Liu Wanqu Zhu Richard Telljohann Jing Zhang Robert E. Monticone Kimberly R. McGraw Changwei Liu Christopher H. Morrell Pablo Garrido‐Gil Jose Luis Labandeira‐Garcia Edward G. Lakatta Mingyi Wang |
| author_facet | Leng Ni Lijuan Liu Wanqu Zhu Richard Telljohann Jing Zhang Robert E. Monticone Kimberly R. McGraw Changwei Liu Christopher H. Morrell Pablo Garrido‐Gil Jose Luis Labandeira‐Garcia Edward G. Lakatta Mingyi Wang |
| author_sort | Leng Ni |
| collection | DOAJ |
| description | Background Age‐associated aortic remodeling includes a marked increase in intimal medial thickness (IMT), associated with signs of inflammation. Although aortic wall milk fat globule–epidermal growth factor VIII (MFG‐E8) increases with age, and is associated with aortic inflammation, it is not known whether MFG‐E8 is required for the age‐associated increase in aortic IMT. Here, we tested whether MFG‐E8 is required for the age‐associated increase in aortic IMT. Methods and Results To determine the role of MFG‐E8 in the age‐associated increase of IMT, we compared aortic remodeling in adult (20‐week) and aged (96‐week) MFG‐E8 (−/−) knockout and age matched wild‐type (WT) littermate mice. The average aortic IMT increased with age in the WT from 50±10 to 70±20 μm (P<0.0001) but did not significantly increase with age in MFG‐E8 knockout mice. Because angiotensin II signaling is implicated as a driver of age‐associated increase in IMT, we infused 30‐week‐old MFG‐E8 knockout and age‐matched littermate WT mice with angiotensin II or saline via osmotic mini‐pumps to determine whether MFG‐E8 is required for angiotensin II–induced aortic remodeling. (1) In WT mice, angiotensin II infusion substantially increased IMT, elastic lamina degradation, collagen deposition, and the proliferation of vascular smooth muscle cells; in contrast, these effects were significantly reduced in MFG‐E8 KO mice; (2) On a molecular level, angiotensin II treatment significantly increased the activation and expression of matrix metalloproteinase type 2, transforming growth factor beta 1, and its downstream signaling molecule phosphorylated mother against decapentaplegic homolog 2, and collagen type I production in WT mice; however, in the MFG‐E8 knockout mice, these molecular effects were significantly reduced; and (3) in WT mice, angiotensin II increased levels of aortic inflammatory markers phosphorylated nuclear factor‐kappa beta p65, monocyte chemoattractant protein 1, tumor necrosis factor alpha, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 molecular expression, while in contrast, these inflammatory markers did not change in knockout mice. Conclusions Thus, MFG‐E8 is required for both age‐associated proinflammatory aortic remodeling and also for the angiotensin II–dependent induction in younger mice of an aortic inflammatory phenotype observed in advanced age. Targeting MFG‐E8 would be a novel molecular approach to curb adverse arterial remodeling. |
| first_indexed | 2024-04-12T18:56:03Z |
| format | Article |
| id | doaj.art-bf073e5d078f47adae6b593d9d3cd4ae |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-12T18:56:03Z |
| publishDate | 2022-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-bf073e5d078f47adae6b593d9d3cd4ae2022-12-22T03:20:20ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802022-09-01111710.1161/JAHA.121.022574Inflammatory Role of Milk Fat Globule–Epidermal Growth Factor VIII in Age‐Associated Arterial RemodelingLeng Ni0Lijuan Liu1Wanqu Zhu2Richard Telljohann3Jing Zhang4Robert E. Monticone5Kimberly R. McGraw6Changwei Liu7Christopher H. Morrell8Pablo Garrido‐Gil9Jose Luis Labandeira‐Garcia10Edward G. Lakatta11Mingyi Wang12Laboratory of Cardiovascular Science, National Institution on Aging National Institutes of Health, Biomedical Research Center (BRC) Baltimore MDLaboratory of Cardiovascular Science, National Institution on Aging National Institutes of Health, Biomedical Research Center (BRC) Baltimore MDLaboratory of Cardiovascular Science, National Institution on Aging National Institutes of Health, Biomedical Research Center (BRC) Baltimore MDLaboratory of Cardiovascular Science, National Institution on Aging National Institutes of Health, Biomedical Research Center (BRC) Baltimore MDLaboratory of Cardiovascular Science, National Institution on Aging National Institutes of Health, Biomedical Research Center (BRC) Baltimore MDLaboratory of Cardiovascular Science, National Institution on Aging National Institutes of Health, Biomedical Research Center (BRC) Baltimore MDLaboratory of Cardiovascular Science, National Institution on Aging National Institutes of Health, Biomedical Research Center (BRC) Baltimore MDDepartment of Vascular Surgery, Peking Union Medical College Hospital Peking Union Medical College & Chinese Academy of Medical Sciences Beijing ChinaLaboratory of Cardiovascular Science, National Institution on Aging National Institutes of Health, Biomedical Research Center (BRC) Baltimore MDResearch Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS University of Santiago de Compostela SpainResearch Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS University of Santiago de Compostela SpainLaboratory of Cardiovascular Science, National Institution on Aging National Institutes of Health, Biomedical Research Center (BRC) Baltimore MDLaboratory of Cardiovascular Science, National Institution on Aging National Institutes of Health, Biomedical Research Center (BRC) Baltimore MDBackground Age‐associated aortic remodeling includes a marked increase in intimal medial thickness (IMT), associated with signs of inflammation. Although aortic wall milk fat globule–epidermal growth factor VIII (MFG‐E8) increases with age, and is associated with aortic inflammation, it is not known whether MFG‐E8 is required for the age‐associated increase in aortic IMT. Here, we tested whether MFG‐E8 is required for the age‐associated increase in aortic IMT. Methods and Results To determine the role of MFG‐E8 in the age‐associated increase of IMT, we compared aortic remodeling in adult (20‐week) and aged (96‐week) MFG‐E8 (−/−) knockout and age matched wild‐type (WT) littermate mice. The average aortic IMT increased with age in the WT from 50±10 to 70±20 μm (P<0.0001) but did not significantly increase with age in MFG‐E8 knockout mice. Because angiotensin II signaling is implicated as a driver of age‐associated increase in IMT, we infused 30‐week‐old MFG‐E8 knockout and age‐matched littermate WT mice with angiotensin II or saline via osmotic mini‐pumps to determine whether MFG‐E8 is required for angiotensin II–induced aortic remodeling. (1) In WT mice, angiotensin II infusion substantially increased IMT, elastic lamina degradation, collagen deposition, and the proliferation of vascular smooth muscle cells; in contrast, these effects were significantly reduced in MFG‐E8 KO mice; (2) On a molecular level, angiotensin II treatment significantly increased the activation and expression of matrix metalloproteinase type 2, transforming growth factor beta 1, and its downstream signaling molecule phosphorylated mother against decapentaplegic homolog 2, and collagen type I production in WT mice; however, in the MFG‐E8 knockout mice, these molecular effects were significantly reduced; and (3) in WT mice, angiotensin II increased levels of aortic inflammatory markers phosphorylated nuclear factor‐kappa beta p65, monocyte chemoattractant protein 1, tumor necrosis factor alpha, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 molecular expression, while in contrast, these inflammatory markers did not change in knockout mice. Conclusions Thus, MFG‐E8 is required for both age‐associated proinflammatory aortic remodeling and also for the angiotensin II–dependent induction in younger mice of an aortic inflammatory phenotype observed in advanced age. Targeting MFG‐E8 would be a novel molecular approach to curb adverse arterial remodeling.https://www.ahajournals.org/doi/10.1161/JAHA.121.022574age‐associated aortic remodelingangiotensin II signalinginflammationintimal medial thickeningmilk fat globule–epidermal growth factor 8 |
| spellingShingle | Leng Ni Lijuan Liu Wanqu Zhu Richard Telljohann Jing Zhang Robert E. Monticone Kimberly R. McGraw Changwei Liu Christopher H. Morrell Pablo Garrido‐Gil Jose Luis Labandeira‐Garcia Edward G. Lakatta Mingyi Wang Inflammatory Role of Milk Fat Globule–Epidermal Growth Factor VIII in Age‐Associated Arterial Remodeling Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease age‐associated aortic remodeling angiotensin II signaling inflammation intimal medial thickening milk fat globule–epidermal growth factor 8 |
| title | Inflammatory Role of Milk Fat Globule–Epidermal Growth Factor VIII in Age‐Associated Arterial Remodeling |
| title_full | Inflammatory Role of Milk Fat Globule–Epidermal Growth Factor VIII in Age‐Associated Arterial Remodeling |
| title_fullStr | Inflammatory Role of Milk Fat Globule–Epidermal Growth Factor VIII in Age‐Associated Arterial Remodeling |
| title_full_unstemmed | Inflammatory Role of Milk Fat Globule–Epidermal Growth Factor VIII in Age‐Associated Arterial Remodeling |
| title_short | Inflammatory Role of Milk Fat Globule–Epidermal Growth Factor VIII in Age‐Associated Arterial Remodeling |
| title_sort | inflammatory role of milk fat globule epidermal growth factor viii in age associated arterial remodeling |
| topic | age‐associated aortic remodeling angiotensin II signaling inflammation intimal medial thickening milk fat globule–epidermal growth factor 8 |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.121.022574 |
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