Developmental endothelial locus-1 protects from hypertension-induced cardiovascular remodeling via immunomodulation.
Developmental endothelial locus-1 protects from hypertension-induced cardiovascular remodeling via immunomodulation.
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DOI：
10.1172/jci126155
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发表时间：
2022-03-15
期刊：
影响因子：
--
通讯作者：
Kopaliani I
中科院分区：
文献类型：
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作者：
Failer T;Amponsah-Offeh M;Neuwirth A;Kourtzelis I;Subramanian P;Mirtschink P;Peitzsch M;Matschke K;Tugtekin SM;Kajikawa T;Li X;Steglich A;Gembardt F;Wegner AC;Hugo C;Hajishengallis G;Chavakis T;Deussen A;Todorov V;Kopaliani I
炎症在高血压相关心血管疾病中的致病作用是显而易见的，需要开发特定的免疫调节疗法。我们检测了内源性抗炎因子--发育内皮细胞基因座-1(Del-1)对血管紧张素II-(AngII-)和脱氧皮质酮-醋酸盐(DOCA-盐)诱导的心血管器官损伤和高血压的治疗作用及其机制。通过使用内皮细胞高表达Del-1的小鼠(EC-Del1小鼠)和通过注射重组Del-1在小鼠中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丢失。Del-1还保护小鼠心脏向心性肥厚和间质及血管周围冠状动脉纤维化，并改善左心功能和心肌冠脉血流灌注。Del-1预防了主动脉僵硬，并消除了高血压的进展。机制上，Del-1通过抑制αvβ3整合素依赖的小鼠和人离体主动脉中原-MMP2的激活而发挥作用。此外，Del-1可稳定αv FoxP3整合素依赖的β细胞数和IL-10水平，这与减少炎症细胞在心血管器官中的募集和促炎细胞因子的产生有关。已证实的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使Del-1成为一种潜在的治疗因素。
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.