Developmental endothelial locus-1 protects from hypertension-induced cardiovascular remodeling via immunomodulation
Theresa Failer, … , Vladimir Todorov, Irakli Kopaliani
Theresa Failer, … , Vladimir Todorov, Irakli Kopaliani
Published February 8, 2022
Citation Information: J Clin Invest. 2022;132(6):e126155. https://doi.org/10.1172/JCI126155.
View: Text | PDF | Corrigendum
Research Article Cardiology Inflammation

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 antiinflammatory factor, in angiotensin II– (ANGII–) and deoxycorticosterone acetate–salt–induced (DOCA-salt–induced) cardiovascular organ damage and hypertension. By using mice with endothelial overexpression of DEL-1 (EC-Del1 mice) 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 and 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 recruitment of inflammatory cells and reduced production of proinflammatory 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.

Authors

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

×

Figure 14

DEL-1 inhibits αvβ3 integrin–dependent activation of latent pro-MMP2.

Options: View larger image (or click on image) Download as PowerPoint
DEL-1 inhibits αvβ3 integrin–dependent activation of latent pro-MMP2. Th...
Thoracic aorta was isolated from WT and EC-Del1 mice and stimulated with ANGII/ET1, followed by assessment of latent pro- and active MMP2 (A). Stimulation of isolated aorta from WT and EC-Del1 mice without endothelium (B). ANGII/ET1-stimulated aortas of WT mice pretreated with Fc, DEL-1–Fc, or DEL-1–RGE–Fc (C). ANGII/ET1–stimulated aortas of WT mice pretreated with plasma of EC-Del1 mice (D). Cultured human aortic SMCs pretreated with plasmas of WT mice injected with Fc, DEL-1–Fc, DEL-1–RGE–Fc, or plasma of EC-Del1 mice and then stimulated with ANGII/ET1 (E). Cultured human aortic SMCs pretreated with Fc, DEL-1–Fc, DEL-1–RGE–Fc, or pharmacological αvβ3 integrin cilengitide and then stimulated with ANGII/ET1 (F) (A–F n = 4 independent experiments). Data are represented as mean ± SEM. **P < 0.01, 1-way ANOVA with Bonferroni’s post hoc test to adjust for multiple comparisons.