Developmental endothelial locus-1 protects from hypertension-induced cardiovascular remodeling via immunomodulation

Theresa Failer; Michael Amponsah-Offeh; Aleš Neuwirth; Ioannis Kourtzelis; Pallavi Subramanian; Peter Mirtschink; Mirko Peitzsch; Klaus Matschke; Sems M Tugtekin; Tetsuhiro Kajikawa; Xiaofei Li; Anne Steglich; Florian Gembardt; Annika C Wegner; Christian Hugo; George Hajishengallis; Triantafyllos Chavakis; Andreas Deussen; Vladimir Todorov; Irakli Kopaliani

doi:10.1172/JCI126155

Developmental endothelial locus-1 protects from hypertension-induced cardiovascular remodeling via immunomodulation

Theresa Failer, Michael Amponsah-Offeh, Aleš Neuwirth, Ioannis Kourtzelis, Pallavi Subramanian, Peter Mirtschink, Mirko Peitzsch, Klaus Matschke, Sems M Tugtekin, Tetsuhiro Kajikawa, Xiaofei Li, Anne Steglich, Florian Gembardt, Annika C Wegner, Christian Hugo, George Hajishengallis, Triantafyllos Chavakis, Andreas Deussen, Vladimir Todorov, Irakli Kopaliani

The Hull York Medical School

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	e126155
Number of pages	25
Journal	Journal of Clinical Investigation
Volume	132
Issue number	6
Early online date	8 Feb 2022
DOIs	https://doi.org/10.1172/JCI126155
Publication status	Published - 15 Mar 2022

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126155.1-20220204092302-covered-e0fd13ba177f913fd3156f593ead4cfd
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Failer, T., Amponsah-Offeh, M., Neuwirth, A., Kourtzelis, I., Subramanian, P., Mirtschink, P., Peitzsch, M., Matschke, K., Tugtekin, S. M., Kajikawa, T., Li, X., Steglich, A., Gembardt, F., Wegner, A. C., Hugo, C., Hajishengallis, G., Chavakis, T., Deussen, A., Todorov, V., & Kopaliani, I. (2022). Developmental endothelial locus-1 protects from hypertension-induced cardiovascular remodeling via immunomodulation. Journal of Clinical Investigation, 132(6), Article e126155. https://doi.org/10.1172/JCI126155

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title = "Developmental endothelial locus-1 protects from hypertension-induced cardiovascular remodeling via immunomodulation",

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.",

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Failer, T, Amponsah-Offeh, M, Neuwirth, A, Kourtzelis, I, Subramanian, P, Mirtschink, P, Peitzsch, M, Matschke, K, Tugtekin, SM, Kajikawa, T, Li, X, Steglich, A, Gembardt, F, Wegner, AC, Hugo, C, Hajishengallis, G, Chavakis, T, Deussen, A, Todorov, V & Kopaliani, I 2022, 'Developmental endothelial locus-1 protects from hypertension-induced cardiovascular remodeling via immunomodulation', Journal of Clinical Investigation, vol. 132, no. 6, e126155. https://doi.org/10.1172/JCI126155

TY - JOUR

T1 - Developmental endothelial locus-1 protects from hypertension-induced cardiovascular remodeling via immunomodulation

AU - Failer, Theresa

AU - Amponsah-Offeh, Michael

AU - Neuwirth, Aleš

AU - Kourtzelis, Ioannis

AU - Subramanian, Pallavi

AU - Mirtschink, Peter

AU - Peitzsch, Mirko

AU - Matschke, Klaus

AU - Tugtekin, Sems M

AU - Kajikawa, Tetsuhiro

AU - Li, Xiaofei

AU - Steglich, Anne

AU - Gembardt, Florian

AU - Wegner, Annika C

AU - Hugo, Christian

AU - Hajishengallis, George

AU - Chavakis, Triantafyllos

AU - Deussen, Andreas

AU - Todorov, Vladimir

AU - Kopaliani, Irakli

PY - 2022/3/15

Y1 - 2022/3/15

N2 - 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.

AB - 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.

U2 - 10.1172/JCI126155

DO - 10.1172/JCI126155

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