Therapeutic role of anti-inflammatory developmental endothelial locus-1 (Del-1) in angiotensin II-induced cardiovascular degeneration and hypertension

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Hypertension is a major risk factor for development of cardiovascular diseases, which cause the largest fraction of deaths worldwide. Hypertension causes aortic stiffness, which further augments hypertension and is associated with hypertrophic cardiac remodeling which may result in coronary insufficiency. Aortic stiffness may also precede onset of hypertension. Therefore, it is used as a prognostic marker for development of cardiovascular diseases independent of hypertension. This compels aortic stiffness as an important therapeutic target. Recently, the prominent role of inflammation, triggered both by monocytes and T-cells, as well as interleukin-17 (IL-17), for the development of aortic stiffness and cardiac hypertrophy has been established. A leading role of inflammation has been conclusively demonstrated in various genetic mouse models, in which aortic stiffness and cardiac hypertrophy were induced with angiotensin II (ANGII) stimulation. This has led to a new therapeutic concept for cardiovascular diseases, which strongly suggests an anti-inflammatory approach. However, unspecific immunosuppression may cause more adverse rather than desired therapeutic effects. Therefore, key elements of inflammation associated with development of hypertension and cardiovascular diseases must be pinpointed to establish specific preventive or therapeutic measures. Developmental endothelial locus-1 (Del-1) is a potent endogenous anti-inflammatory factor. It inhibits infiltration of vessels and tissues with leukocytes and limits IL-17-dependent inflammation. Our preliminary work strongly indicates that Del-1 potently prevents ANGII-induced aortic stiffness and cardiac hypertrophy, as well as development of hypertension. This project aims to thoroughly investigate the mechanisms of action of Del-1 in prevention of cardiovascular remodeling and subsequently elucidate its therapeutic potential.