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

• Published in: The Journal of clinical investigation Vol. 132; no. 6; pp. 1 - 24
• Main Authors: Failer, Theresa, Amponsah-Offeh, Michael, Neuwirth, Aleš, Kourtzelis, Ioannis, Subramanian, Pallavi, Mirtschink, Peter, Peitzsch, Mirko, Matschke, Klaus, Tugtekin, Sems M., Kajikawa, Tetsuhiro, Li, Xiaofei, Steglich, Anne, Gembardt, Florian, Wegner, Annika C., Hugo, Christian, Hajishengallis, George, Chavakis, Triantafyllos, Deussen, Andreas, Todorov, Vladimir, Kopaliani, Irakli
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.03.2022
• Subjects: Acetic acid; Angiotensin; Angiotensin II; Animals; Aorta; Biomedical research; Calcium-Binding Proteins - metabolism; Cardiology; Cardiomegaly; Cardiomyocytes; Cardiovascular diseases; CD25 antigen; Cell Adhesion Molecules - metabolism; Collagen; Complications and side effects; Coronary vessels; Cytokines; Development and progression; Elastin; Endothelium; Experiments; Fibrosis; Foxp3 protein; Gelatinase A; Glycoproteins; Health aspects; Heart; Heart diseases; Hypertension; Hypertension - complications; Hypertrophy; Immune response; Immunomodulation; Immunomodulation - genetics; Inflammation; Integrins; Interleukin 10; Lymphocytes T; Mice; Multiple sclerosis; Perfusion; Physiological aspects; Regulation; Salt; Ventricle; Ventricular Remodeling - genetics; Germany; Hypertension; Cardiovascular disease; Inflammation; Cardiology
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI126155

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.