Failer, Theresa, Amponsah-Offeh, Michael, Neuwirth, Aleš et al. (17 more authors) (2022) Developmental endothelial locus-1 protects from hypertension-induced cardiovascular remodeling via immunomodulation. Journal of Clinical Investigation. e126155. ISSN 1558-8238
Abstract
The causative role of inflammation in hypertension-related cardiovascular diseases is evident and calls for development of specific immunomodulatory therapies. We tested the therapeutic efficacy and mechanisms of action of developmental endothelial locus-1 (DEL-1), an endogenous anti-inflammatory factor, in angiotensin-II (ANGII)- and DOCA (deoxycorticosterone acetate)-salt-induced cardiovascular organ damage and hypertension. By using mice with endothelial overexpression of DEL-1 (EC-Del1) and performing preventive and interventional studies by injecting recombinant DEL-1 in mice, we showed that DEL-1 improved endothelial function and abrogated aortic adventitial fibrosis, medial thickening and loss of elastin. DEL-1 also protected the mice from cardiac concentric hypertrophy, interstitial and perivascular coronary fibrosis and improved left-ventricular function and myocardial coronary perfusion. DEL-1 prevented aortic stiffness and abolished the progression of hypertension. Mechanistically, DEL-1 acted by inhibiting αvβ3-integrin dependent activation of pro-MMP2 in mice and in human isolated aorta. Moreover, DEL-1 stabilized αvβ3-integrin dependent CD25+FoxP3+ Treg numbers and IL-10 levels, which were associated with decreased pro-inflammatory cell recruitment of inflammatory cells and reduced production of pro-inflammatory cytokines in cardiovascular organs. The demonstrated effects and immune-modulating mechanisms of DEL-1 in abrogation of cardiovascular remodeling and progression of hypertension identify DEL-1 as a potential therapeutic factor.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | ©2022, The Author(s). |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Hull York Medical School (York) |
Depositing User: | Pure (York) |
Date Deposited: | 10 Feb 2022 11:20 |
Last Modified: | 26 Nov 2024 00:52 |
Published Version: | https://doi.org/10.1172/JCI126155 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1172/JCI126155 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:183482 |
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