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

高血压是心血管疾病发展的主要风险因素，而心血管疾病导致的死亡占全球死亡人数的最大比例。高血压导致主动脉僵硬，从而进一步增加高血压，并与肥厚的心脏重构相关，后者可能导致冠状动脉功能不全。主动脉僵硬也可能是高血压发病的先兆。因此，它被用作独立于高血压的心血管疾病发展的预后标记物。这迫使主动脉僵硬成为一个重要的治疗靶点。最近，由单核细胞和T细胞以及白介素17(IL-17)共同触发的炎症在主动脉僵硬和心肌肥厚的发生中的重要作用已被证实。在血管紧张素II(AngII)刺激诱导的主动脉僵硬和心肌肥大的各种遗传小鼠模型中，炎症已被确凿地证明是主导作用。这导致了一种治疗心血管疾病的新概念，这强烈地表明了一种抗炎方法。然而，非特异性免疫抑制可能会导致更多的不良反应，而不是预期的治疗效果。因此，必须准确定位与高血压和心血管疾病发展相关的炎症的关键因素，以建立具体的预防或治疗措施。发育内皮细胞基因座-1(Del-1)是一种强有力的内源性抗炎因子。它抑制血管和组织与白细胞的渗透，并限制IL-17依赖的炎症。我们的初步工作有力地表明，Del-1有效地预防血管紧张素转换酶诱导的主动脉僵硬和心肌肥厚，以及高血压的发展。本项目旨在深入研究Del-1在预防心血管重构中的作用机制，并随后阐明其治疗潜力。

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.