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一个主要危险因素，而心血管疾病在全世界造成的死亡人数中所占比例最大。高血压引起主动脉僵硬，这进一步增加了高血压，并与肥厚性心脏重构相关，这可能导致冠状动脉功能不全。主动脉僵硬也可能先于高血压发病。因此，它被用作独立于高血压的心血管疾病发展的预后标志物。这迫使主动脉僵硬成为一个重要的治疗靶点。最近，单核细胞和t细胞以及白细胞介素-17 （IL-17）引发的炎症在主动脉僵硬和心脏肥厚的发展中发挥了突出作用。在各种遗传小鼠模型中，炎症的主导作用已经得到了最终证明，在这些模型中，血管紧张素II （ANGII）刺激诱导主动脉僵硬和心脏肥厚。这导致了心血管疾病的一种新的治疗概念，强烈建议采用抗炎方法。然而，非特异性免疫抑制可能导致更多的不良而不是期望的治疗效果。因此，必须确定与高血压和心血管疾病发展相关的炎症的关键因素，以建立特定的预防或治疗措施。发育内皮基因座-1 （Del-1）是一种有效的内源性抗炎因子。它抑制血管和白细胞组织的浸润，限制il -17依赖性炎症。我们的初步工作有力地表明，Del-1可以有效地预防血管内皮增生引起的主动脉僵硬和心脏肥厚，以及高血压的发生。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，并进一步阐明其治疗潜力。

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.