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Transactivation of RAGE mediates angiotensin-induced inflammation and atherogenesis
Raelene J. Pickering, … , Kevin D.G. Pfleger, Merlin C. Thomas
Raelene J. Pickering, … , Kevin D.G. Pfleger, Merlin C. Thomas
Published December 10, 2018
Citation Information: J Clin Invest. 2019;129(1):406-421. https://doi.org/10.1172/JCI99987.
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Research Article Cell biology Vascular biology

Transactivation of RAGE mediates angiotensin-induced inflammation and atherogenesis

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Abstract

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.

Authors

Raelene J. Pickering, Christos Tikellis, Carlos J. Rosado, Despina Tsorotes, Alexandra Dimitropoulos, Monique Smith, Olivier Huet, Ruth M. Seeber, Rekhati Abhayawardana, Elizabeth K.M. Johnstone, Jonathan Golledge, Yutang Wang, Karin A. Jandeleit-Dahm, Mark E. Cooper, Kevin D.G. Pfleger, Merlin C. Thomas

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Figure 2

Differential effects of exposure to Ang II (1 μM) in PMAECs from C57BL/6J or Ager-KO mice.

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Differential effects of exposure to Ang II (1 μM) in PMAECs from C57BL/6...
(A) Induction of hydrogen peroxide production in a flow chamber. (B) Induction of the canonical and noncanonical NF-κB signaling gene markers CXCL12 and CXCL2, respectively, following exposure to Ang II or the prototypical NF-κB–inducing cytokine TNF-α (1 ng/ml for 24 h). (C) Induction of gene expression of proatherogenic mediators, including adhesion molecules, inflammatory chemokines, and cytokines, following exposure to Ang II (1 μM for 2 h). (D) Quantitation of labeled THP-1 monocytes adherent to a monolayer of PMAECs from C57BL/6J and Ager-KO mice with or without Ang II pretreatment (1 μM for 2 h). (E) Induction of ICAM-1 expression by Ang II (1 μM for 2 h) and the RAGE ligand S100A8/A9 (2 μg/ml for 2 h) following silencing of RAGE or p65 expression by an siRNA (see Supplemental Figure 2, A–C, for details). (F) Induction of classical Gq inositol phosphate signaling, as estimated by the accumulation of IP1 at 2 hours. Data are presented as the mean ± SD. n = 6–8 per group. *P < 0.05 versus C57BL/6J; #P < 0.05 versus C57BL/6J plus Ang II; §P < 0.05 versus C57BL/6J plus S100A8/A9. P values were determined by 2-way ANOVA.
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