血管紧张素II介导的T细胞功能异常参与高血压心脏重构的作用机制研究

Our previous studies have found that deficiency of C3aR (Complement 3a receptor) and C5aR (DKO) prevents Angiotensin (Ang) II-induced hypertension and renal/vascular damage, likely through regulating Regulatory T cells (Tregs) function (2018 Circ Res). However, the precise mechanism of Ang II-induced T cells dysfunction in hypertensive cardiac remodeling is still unclear. In this study, we hypothesized that C3aR and C5aR contribute to Ang II-induced Tregs dysfunction, leading to cardiac inflammation and fibrosis. Based on the above, we explore that: 1) Tregs dysfunction induced by Ang II and the involvement mechanism of C3aR/C5aR in the regulation of Tregs function; 2) the effects of Tregs dysfunction on cardiac inflammation and fibrosis in mouse models induced by Ang II; 3) whether Tregs were involved in the improvement of cardiac inflammation and fibrosis induced by Ang II in DKO mice; 4) the impact of deletion Tregs in DKO mice on hypertensive cardiac damage induced by Ang II.

我们前期研究发现血管紧张素II（Ang II）灌注联合缺失补体3a受体（Complement 3a receptor，C3aR）和C5aR（DKO）的小鼠后，抑制血压升高，肾脏损伤和血管重塑改善，且依赖于DKO调节性T细胞（Tregs）作用（2018 Circ Res）。但Ang II如何介导T细胞功能异常，是否涉及高血压诱导的心脏重构过程尚不清楚。本研究假设C3aR和C5aR参与Ang II介导的Tregs功能异常，从而导致心脏炎症及纤维化发生。在此基础上将深入探讨：1）Ang II诱导的Tregs功能异常，以及C3aR和C5aR参与其中的具体分子机制；2）Ang II诱导的心脏损伤小鼠模型中，Tregs功能失常对心脏炎症、纤维化的影响；3）DKO小鼠对Ang II诱导的心脏炎症及纤维化改善是否涉及Tregs；4）整体干预DKO小鼠体内Tregs对Ang II诱导的高血压心脏损伤的影响。

补体激活被认为是肥胖相关代谢紊乱的病理进展的重点；然而，它在适应性产热中的作用却很少被探讨。 在这里，我们发现补体C3a受体（C3aR）和C5a受体（C5aR）是控制脂肪细胞棕色化和能量平衡的关键开关。 我们发现，C3aR和C5aR联合敲除比单独敲除更能增加冷刺激的脂肪细胞棕色化和减轻饮食诱导的肥胖。 在机制上，C3aR和C5aR的缺失增加了冷刺激或高脂肪饮食（HFD）期间皮下白色脂肪组织中调节性T细胞（Tregs）的积累。 被激活的Tregs产生腺苷，腺苷被脂肪细胞衍生的腺苷脱氨酶（ADA）转化为肌苷。 肌苷通过激活腺苷A2a受体（A2aR）促进脂肪细胞棕色化。 这些结果揭示了补体在控制适应性产热方面的一种新的调节机制，并提示靶向C3aR/C5aR通路可能是治疗肥胖和代谢疾病的一种治疗策略。

内容获取失败，请点击重试