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
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 [...]