1. Developmental endothelial locus-1 protects from hypertension-induced cardiovascular remodeling via immunomodulation
- Author
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Failer, Theresa, Amponsah-Offeh, Michael, Neuwirth, Ales, Kourtzelis, loannis, 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, and Kopaliani, Irakli
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Heart diseases -- Development and progression ,Glycoproteins -- Health aspects -- Physiological aspects ,Inflammation -- Development and progression -- Complications and side effects ,Endothelium -- Health aspects -- Physiological aspects ,Immune response -- Regulation ,Hypertension -- Complications and side effects -- Development and progression ,Health care industry - 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 Il- (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 [[alpha].sub.v][[beta].sub.3] integrin-dependent activation of pro-MMP2 in mice and in human isolated aorta. Moreover, DEL-1 stabilized [[alpha].sub.v][[beta].sub.3] integrin-dependent [CD25.sup.+][FoxP3.sup.+] 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., Introduction Hypertension is a major risk factor for development of cardiovascular diseases, which cause the highest number of deaths worldwide among noninfectious diseases (1). Currently, over one billion adults are [...]
- Published
- 2022
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