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

抗炎发育内皮基因座-1 (Del-1) 在血管紧张素 II 诱导的心血管变性和高血压中的治疗作用

• 批准号: 405854374
• 负责人: Professor Dr. Irakli Kopaliani
• 金额: --
• 依托单位: Institut für Physiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/405854374?language=en
• 关键词: Therapeutic; role; anti; inflammatory; developmental

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.

高血压是导致心血管疾病的主要危险因素，心血管疾病是全球死亡人数最多的疾病。高血压导致主动脉僵硬，这进一步加重高血压，并与肥厚性心脏重塑相关，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作。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。这迫使主动脉僵硬作为一个重要的治疗目标。最近，已经确定了由单核细胞和T细胞以及白细胞介素-17（IL-17）触发的炎症对于主动脉僵硬和心脏肥大的发展的突出作用。炎症的主导作用已在各种遗传小鼠模型中得到最终证实，其中血管紧张素II（ANGII）刺激诱导主动脉僵硬和心脏肥大。这为心血管疾病带来了一种新的治疗概念，强烈建议采用抗炎方法。然而，非特异性免疫抑制可能会导致更多的不良反应，而不是期望的治疗效果。因此，与高血压和心血管疾病的发展相关的炎症的关键因素必须被精确定位，以建立具体的预防或治疗措施。发育性内皮细胞基因座-1（Del-1）是一种有效的内源性抗炎因子。它抑制白细胞浸润血管和组织，并限制IL-17依赖性炎症。我们的初步工作有力地表明，Del-1有效地防止ANGII诱导的主动脉僵硬和心脏肥大，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。