Department of Physiology and.
Institute for Clinical Chemistry and Laboratory Medicine, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
J Clin Invest. 2022 Mar 15;132(6). doi: 10.1172/JCI126155.
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 II- (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 αvβ3 integrin-dependent activation of pro-MMP2 in mice and in human isolated aorta. Moreover, DEL-1 stabilized αvβ3 integrin-dependent CD25+FoxP3+ 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.
炎症在高血压相关心血管疾病中的致病作用已得到证实,这就需要开发针对炎症的特异性调节疗法。我们检测了发育内皮细胞定位-1(DEL-1)——一种内源性抗炎因子,在血管紧张素 II(ANGII)和脱氧皮质酮醋酸盐盐诱导(DOCA-salt 诱导)心血管器官损伤和高血压中的治疗效果和作用机制。通过使用内皮细胞过表达 DEL-1 的小鼠(EC-Del1 小鼠),并通过在小鼠中注射重组 DEL-1 进行预防和干预研究,我们发现 DEL-1 改善了内皮功能,消除了主动脉外膜纤维化、中膜增厚和弹性蛋白丧失。DEL-1 还保护小鼠免受心脏向心性肥大、间质和血管周围冠状纤维化的影响,改善了左心室功能和心肌冠状灌注。DEL-1 预防了主动脉僵硬并消除了高血压的进展。从机制上讲,DEL-1 通过抑制小鼠和人离体主动脉中 αvβ3 整合素依赖性 pro-MMP2 的激活起作用。此外,DEL-1 稳定了 αvβ3 整合素依赖性 CD25+FoxP3+Treg 数量和 IL-10 水平,这与心血管器官中炎症细胞的募集减少和促炎细胞因子的产生减少有关。DEL-1 在消除心血管重构和高血压进展方面的作用和免疫调节机制表明,DEL-1 是一种有潜力的治疗因子。