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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 3

Functional response to Ang II or S100A8/A9 in the presence or absence of the human AT1 receptor, RAGE constructs, or both.

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Functional response to Ang II or S100A8/A9 in the presence or absence of...
Treatment with Ang II was at a dose of 1 μM for 2 hours, and treatment with S100A8/A9 was at a dose of 2 μg/ml for 2 hours. (A) Induction of inositol phosphate synthesis. (B) NF-κB activation as measured by a chemiluminescent SEAP reporter gene assay, and induction of gene expression of the NF-κB subunit p65 in the presence or absence of full-length human RAGE. (C) Induction of p65 expression following exposure to the RAGE ligand, S100A8/A9 (2 μg/ml for 2 h) in the presence or absence of full-length RAGE. (D) Induction of p65 following exposure to S100A8/A9 or Ang II in PMAECs in the presence or absence of soluble RAGE or a neutralizing antibody targeting the extracellular domain of RAGE. (E) NF-κB activation and the induction of p65 expression in the presence or absence of full-length or N-truncated RAGE constructs in AT1-CHO cells. (F) NF-κB activation and the induction of p65 expression by Ang II in the presence or absence of full-length or C-truncated RAGE constructs in AT1-CHO cells. Data are presented as the mean ± SD. n = 6–8 per group. *P < 0.05 versus AT1-CHO plus vector (pCIneo or mCherry); #P < 0.05 versus AT1-CHO plus full-length RAGE; †P < 0.05 versus AT1-CHO plus full-length RAGE plus Ang II; §P < 0.05 versus AT1-CHO plus RAGE plus S100A8/A9. P values were determined by 2-way ANOVA.

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