Transactivation of RAGE mediates angiotensin-induced inflammation and atherogenesis

Pickering, Raelene J., Tikellis, Christos, Rosado, Carlos J., Tsorotes, Despina, Dimitropoulos, Alexandra, Smith, Monique, Huet, Olivier, Seeber, Ruth M., Abhayawardana, Rekhati, Johnstone, Elizabeth K.M., Golledge, Jonathan, Wang, Yutang, Jandeleit-Dahm, Karin A., Cooper, Mark E., Pfleger, Kevin D.E., and Thomas, Merlin C. (2019) Transactivation of RAGE mediates angiotensin-induced inflammation and atherogenesis. Journal of Clinical Investigation, 129 (1). pp. 406-421.

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Abstract

Activation of the type 1 angiotensin II receptor (AT(1)) triggers proinflammatory signaling through pathways independent of classical Gq signaling that regulate vascular homeostasis. Here, we report that the AT(1) receptor preformed a heteromeric complex with the receptor for advanced glycation endproducts (RAGE). Activation of the AT(1) receptor by angiotensin II (Ang II) triggered transactivation of the cytosolic tail of RAGE and NF-kappa B-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 AT(1) 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 AT(1) receptor as a target for vasculoprotective interventions. As proof of concept, we showed that treatment with the mutant RAGE peptide S391A-RAGE(362-404) was able to inhibit transactivation of RAGE and attenuate Ang II-dependent inflammation and atherogenesis. Furthermore, treatment with WT RAGE(362-404) 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.

Item ID: 56942
Item Type: Article (Research - C1)
ISSN: 1708-8267
Copyright Information: Copyright 2019, American Society for Clinical Investigation.
Funders: National Health and Medical Research Council (NHMRC)
Projects and Grants: NHMRC 1081013, NHMRC 1107555, NHMRC 1059124, NHMRC 1078808, NHMRC 1085842
Date Deposited: 23 Jan 2019 07:33
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3201 Cardiovascular medicine and haematology > 320199 Cardiovascular medicine and haematology not elsewhere classified @ 100%
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