Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia.
Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
J Clin Invest. 2019 Jan 2;129(1):406-421. doi: 10.1172/JCI99987. Epub 2018 Dec 10.
Activation of the type 1 angiotensin II receptor (AT1) triggers proinflammatory signaling through pathways independent of classical Gq signaling that regulate vascular homeostasis. Here, we report that the AT1 receptor preformed a heteromeric complex with the receptor for advanced glycation endproducts (RAGE). Activation of the AT1 receptor by angiotensin II (Ang II) triggered transactivation of the cytosolic tail of RAGE and NF-κB-driven proinflammatory gene expression independently of the liberation of RAGE ligands or the ligand-binding ectodomain of RAGE. The importance of this transactivation pathway was demonstrated by our finding that adverse proinflammatory signaling events induced by AT1 receptor activation were attenuated when RAGE was deleted or transactivation of its cytosolic tail was inhibited. At the same time, classical homeostatic Gq signaling pathways were unaffected by RAGE deletion or inhibition. These data position RAGE transactivation by the AT1 receptor as a target for vasculoprotective interventions. As proof of concept, we showed that treatment with the mutant RAGE peptide S391A-RAGE362-404 was able to inhibit transactivation of RAGE and attenuate Ang II-dependent inflammation and atherogenesis. Furthermore, treatment with WT RAGE362-404 restored Ang II-dependent atherogenesis in Ager/Apoe-KO mice, without restoring ligand-mediated signaling via RAGE, suggesting that the major effector of RAGE activation was its transactivation.
血管紧张素 II 型 1 型受体 (AT1) 的激活通过独立于调节血管稳态的经典 Gq 信号通路的促炎信号通路触发促炎信号。在这里，我们报告 AT1 受体与晚期糖基化终产物受体 (RAGE) 形成异源二聚体复合物。血管紧张素 II (Ang II) 激活 AT1 受体可触发 RAGE 胞质尾的转激活和 NF-κB 驱动的促炎基因表达，而无需 RAGE 配体的释放或 RAGE 配体结合胞外结构域。当 RAGE 缺失或其胞质尾的转激活被抑制时，发现 AT1 受体激活引起的不利促炎信号事件减弱，证明了这种转激活途径的重要性。与此同时，经典的稳态 Gq 信号通路不受 RAGE 缺失或抑制的影响。这些数据将 AT1 受体的 RAGE 转激活定位为血管保护干预的靶点。作为概念验证，我们表明，用突变型 RAGE 肽 S391A-RAGE362-404 治疗能够抑制 RAGE 的转激活，并减轻 Ang II 依赖性炎症和动脉粥样硬化形成。此外，用 WT RAGE362-404 治疗可恢复 Ager/Apoe-KO 小鼠中 Ang II 依赖性动脉粥样硬化形成，而不会通过 RAGE 恢复配体介导的信号转导，表明 RAGE 激活的主要效应物是其转激活。
