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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 know...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9496444/ https://www.ncbi.nlm.nih.gov/pubmed/36000422 http://dx.doi.org/10.1161/JAHA.121.022574 |
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author | Ni, Leng Liu, Lijuan Zhu, Wanqu Telljohann, Richard Zhang, Jing Monticone, Robert E. McGraw, Kimberly R. Liu, Changwei Morrell, Christopher H. Garrido‐Gil, Pablo Labandeira‐Garcia, Jose Luis Lakatta, Edward G. Wang, Mingyi |
author_facet | Ni, Leng Liu, Lijuan Zhu, Wanqu Telljohann, Richard Zhang, Jing Monticone, Robert E. McGraw, Kimberly R. Liu, Changwei Morrell, Christopher H. Garrido‐Gil, Pablo Labandeira‐Garcia, Jose Luis Lakatta, Edward G. Wang, Mingyi |
author_sort | Ni, Leng |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-9496444 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-94964442022-09-30 Inflammatory Role of Milk Fat Globule–Epidermal Growth Factor VIII in Age‐Associated Arterial Remodeling Ni, Leng Liu, Lijuan Zhu, Wanqu Telljohann, Richard Zhang, Jing Monticone, Robert E. McGraw, Kimberly R. Liu, Changwei Morrell, Christopher H. Garrido‐Gil, Pablo Labandeira‐Garcia, Jose Luis Lakatta, Edward G. Wang, Mingyi J Am Heart Assoc Original Research 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. John Wiley and Sons Inc. 2022-08-24 /pmc/articles/PMC9496444/ /pubmed/36000422 http://dx.doi.org/10.1161/JAHA.121.022574 Text en © 2022 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Research Ni, Leng Liu, Lijuan Zhu, Wanqu Telljohann, Richard Zhang, Jing Monticone, Robert E. McGraw, Kimberly R. Liu, Changwei Morrell, Christopher H. Garrido‐Gil, Pablo Labandeira‐Garcia, Jose Luis Lakatta, Edward G. Wang, Mingyi Inflammatory Role of Milk Fat Globule–Epidermal Growth Factor VIII in Age‐Associated Arterial Remodeling |
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 | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9496444/ https://www.ncbi.nlm.nih.gov/pubmed/36000422 http://dx.doi.org/10.1161/JAHA.121.022574 |
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