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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 6

Effects of treatment with mCherry-RAGE362–404 oligopeptides on proinflammatory signaling following exposure to Ang II in vitro, ex vivo, and in vivo.

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Effects of treatment with mCherry-RAGE362–404 oligopeptides on proinflam...
Treatment with Ang II was at a dose of 1 μM.(A) Induction of ICAM-1 and MCP-1 expression in HMEC1 in the presence or absence of plasmids expressing truncated RAGE constructs. (B) Induction of p65 expression in AT1-CHO cells treated with mCherry-RAGE362–404 or mCherry-S391A-RAGE362–404 (0.4 ng/ml). (C) Expression of proinflammatory genes in PMAECs from Ager-KO mice in the presence or absence of mCherry-RAGE362–404 (0.4 ng/ml). (D) Expression of proinflammatory genes in (RAGE-replete) PMAECs induced by Ang II in the presence or absence of mCherry-S391A-RAGE362–404 (0.4 ng/ml). (E) Induction of ICAM-1 expression in PMAECs in the presence or absence of mCherry-S391A-RAGE362–404 (0.4 ng/ml) or irbesartan (1 μM). (F) Induction of ICAM-1 expression in aortae from Apoe-KO and Ager/Apoe-DKO mice in the presence or absence of mCherry-RAGE362–404 or mCherry-S391A-RAGE362–404 (8 ng/ml). (G) Plaque area in aortae from Apoe-KO, Ace2/Apoe-DKO, and Ager/Ace2/Apoe-TKO mice in the presence or absence of mCherry-RAGE362–404 or mCherry-S391A-RAGE362–404 (10 μg/kg i.p. every other day). (H) Plaque area in aortae from diabetic Apoe-KO and Ager/Apoe-DKO mice in the presence or absence of mCherry-RAGE362–404 or mCherry-S391A-RAGE362–404 (10 μg/kg i.p. every other day). Data are presented as the mean ± SD. n = 6–8 group. *P < 0.05 versus pCIneo plus vehicle; #P < 0.05 versus pCIneo plus Ang II; §P < 0.05 versus mCherry plus vehicle; †P < 0.05 versus mCherry plus Ang II; ‡P < 0.05 versus mCherry-RAGE362–404 plus Ang II; **P < 0.05 versus Ace2/Apoe-DKO plus mCherry; ††P < 0.05 versus Apoe plus TAT-mCherry. P values were determined by 2-way ANOVA.

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