Genome-Wide Search Links Senescence-Associated Secretory Proteins With Susceptibility for Coronary Artery Disease in Mouse and Human
© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com..
Advanced age is an independent risk factor for coronary artery disease (CAD), the leading global cause of mortality. Senescent vascular cells in the atherosclerotic plaques exhibit senescence-associated secretory phenotype (SASP). How SASP contributes to atherosclerosis and CAD, however, remains unclear. Here, we integrated RNA-array datasets of senescent human coronary arterial endothelial cells (HCAECs) and aortic smooth muscle cells (HASMCs) as well as genome-wide association data for CAD. We identified 26 genes from HCAECs and 6 genes from HASMCs related to SASP and CAD in both in-house and published datasets. Of which, Cystatin C (CST3), a CAD susceptibility gene, was found to be expressed in both HCAECs and HASMCs, thus, it was prioritized for further investigation. We demonstrated it was significantly elevated in senescent vascular cells, aged arteries, and early atherosclerosis. In vitro experiments showed that CST3 enhances the monocyte-endothelial cell adhesion. Additionally, ligand-receptor pairing analyses revealed two important pathways, COL4A1-ITGA1 and LPL-LRP1 pathways, linked to the critical processes in the development of atherosclerosis, including cell adhesion, inflammation response, extracellular matrix organization, and lipid metabolism. We further demonstrated a reduced monocyte-endothelial cell adhesion following the knockdown of COL4A1 or ITGA1 and a significantly increased expression of COL4A1, ITGA1, and LPL in arterial intima of aged mice and ApoE-/- mice. Our findings demonstrate that vascular cell-derived SASP proteins increase the CAD susceptibility and identify CST3 functionally contributing to atherosclerosis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:79 |
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| Enthalten in: |
The journals of gerontology. Series A, Biological sciences and medical sciences - 79(2024), 5 vom: 01. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhu, Yuan-Zheng [VerfasserIn] |
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| Links: |
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| Themen: |
Atherosclerosis |
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| Anmerkungen: |
Date Completed 08.04.2024 Date Revised 08.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/gerona/glae070 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Advanced age is an independent risk factor for coronary artery disease (CAD), the leading global cause of mortality. Senescent vascular cells in the atherosclerotic plaques exhibit senescence-associated secretory phenotype (SASP). How SASP contributes to atherosclerosis and CAD, however, remains unclear. Here, we integrated RNA-array datasets of senescent human coronary arterial endothelial cells (HCAECs) and aortic smooth muscle cells (HASMCs) as well as genome-wide association data for CAD. We identified 26 genes from HCAECs and 6 genes from HASMCs related to SASP and CAD in both in-house and published datasets. Of which, Cystatin C (CST3), a CAD susceptibility gene, was found to be expressed in both HCAECs and HASMCs, thus, it was prioritized for further investigation. We demonstrated it was significantly elevated in senescent vascular cells, aged arteries, and early atherosclerosis. In vitro experiments showed that CST3 enhances the monocyte-endothelial cell adhesion. Additionally, ligand-receptor pairing analyses revealed two important pathways, COL4A1-ITGA1 and LPL-LRP1 pathways, linked to the critical processes in the development of atherosclerosis, including cell adhesion, inflammation response, extracellular matrix organization, and lipid metabolism. We further demonstrated a reduced monocyte-endothelial cell adhesion following the knockdown of COL4A1 or ITGA1 and a significantly increased expression of COL4A1, ITGA1, and LPL in arterial intima of aged mice and ApoE-/- mice. Our findings demonstrate that vascular cell-derived SASP proteins increase the CAD susceptibility and identify CST3 functionally contributing to atherosclerosis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Atherosclerosis | |
| 650 | 4 | |a Cardiovascular disease | |
| 650 | 4 | |a Cellular senescence | |
| 650 | 4 | |a Cystatin C | |
| 650 | 4 | |a Vascular aging | |
| 650 | 7 | |a Proteins |2 NLM | |
| 700 | 1 | |a Liu, Jian-Kun |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xue-Er |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Zhen-Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Lu-Qin |e verfasserin |4 aut | |
| 700 | 1 | |a Wan, Qin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Ya |e verfasserin |4 aut | |
| 700 | 1 | |a Saeed, Muhammad |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, An-Dong |e verfasserin |4 aut | |
| 700 | 1 | |a Tian, Xiao-Li |e verfasserin |4 aut | |
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