Radical Roles for RAGE in the Pathogenesis of Oxidative Stress in Cardiovascular Diseases and Beyond
Oxidative stress is a central mechanism by which the receptor for advanced glycation endproducts (RAGE) mediates its pathological effects. Multiple experimental inquiries in RAGE-expressing cultured cells have demonstrated that ligand-RAGE interaction mediates generation of reactive oxygen species (...
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doaj-59ab2a253c614e9d852c5932cb767bfa2020-11-25T01:26:16ZengMDPI AGInternational Journal of Molecular Sciences1422-00672013-10-011410198911991010.3390/ijms141019891Radical Roles for RAGE in the Pathogenesis of Oxidative Stress in Cardiovascular Diseases and BeyondRadha AnanthakrishnanRavichandran RamasamyKaren M. O'SheaCarmen Hurtado del PozoGurdip DaffuAnn Marie SchmidtOxidative stress is a central mechanism by which the receptor for advanced glycation endproducts (RAGE) mediates its pathological effects. Multiple experimental inquiries in RAGE-expressing cultured cells have demonstrated that ligand-RAGE interaction mediates generation of reactive oxygen species (ROS) and consequent downstream signal transduction and regulation of gene expression. The primary mechanism by which RAGE generates oxidative stress is via activation of NADPH oxidase; amplification mechanisms in the mitochondria may further drive ROS production. Recent studies indicating that the cytoplasmic domain of RAGE binds to the formin mDia1 provide further support for the critical roles of this pathway in oxidative stress; mDia1 was required for activation of rac1 and NADPH oxidase in primary murine aortic smooth muscle cells treated with RAGE ligand S100B. In vivo, in multiple distinct disease models in animals, RAGE action generates oxidative stress and modulates cellular/tissue fate in range of disorders, such as in myocardial ischemia, atherosclerosis, and aneurysm formation. Blockade or genetic deletion of RAGE was shown to be protective in these settings. Indeed, beyond cardiovascular disease, evidence is accruing in human subjects linking levels of RAGE ligands and soluble RAGE to oxidative stress in disorders such as doxorubicin toxicity, acetaminophen toxicity, neurodegeneration, hyperlipidemia, diabetes, preeclampsia, rheumatoid arthritis and pulmonary fibrosis. Blockade of RAGE signal transduction may be a key strategy for the prevention of the deleterious consequences of oxidative stress, particularly in chronic disease.http://www.mdpi.com/1422-0067/14/10/19891receptor for advanced glycation endproductnon-enzymatic glycationinflammationredox signaling |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Radha Ananthakrishnan Ravichandran Ramasamy Karen M. O'Shea Carmen Hurtado del Pozo Gurdip Daffu Ann Marie Schmidt |
spellingShingle |
Radha Ananthakrishnan Ravichandran Ramasamy Karen M. O'Shea Carmen Hurtado del Pozo Gurdip Daffu Ann Marie Schmidt Radical Roles for RAGE in the Pathogenesis of Oxidative Stress in Cardiovascular Diseases and Beyond International Journal of Molecular Sciences receptor for advanced glycation endproduct non-enzymatic glycation inflammation redox signaling |
author_facet |
Radha Ananthakrishnan Ravichandran Ramasamy Karen M. O'Shea Carmen Hurtado del Pozo Gurdip Daffu Ann Marie Schmidt |
author_sort |
Radha Ananthakrishnan |
title |
Radical Roles for RAGE in the Pathogenesis of Oxidative Stress in Cardiovascular Diseases and Beyond |
title_short |
Radical Roles for RAGE in the Pathogenesis of Oxidative Stress in Cardiovascular Diseases and Beyond |
title_full |
Radical Roles for RAGE in the Pathogenesis of Oxidative Stress in Cardiovascular Diseases and Beyond |
title_fullStr |
Radical Roles for RAGE in the Pathogenesis of Oxidative Stress in Cardiovascular Diseases and Beyond |
title_full_unstemmed |
Radical Roles for RAGE in the Pathogenesis of Oxidative Stress in Cardiovascular Diseases and Beyond |
title_sort |
radical roles for rage in the pathogenesis of oxidative stress in cardiovascular diseases and beyond |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2013-10-01 |
description |
Oxidative stress is a central mechanism by which the receptor for advanced glycation endproducts (RAGE) mediates its pathological effects. Multiple experimental inquiries in RAGE-expressing cultured cells have demonstrated that ligand-RAGE interaction mediates generation of reactive oxygen species (ROS) and consequent downstream signal transduction and regulation of gene expression. The primary mechanism by which RAGE generates oxidative stress is via activation of NADPH oxidase; amplification mechanisms in the mitochondria may further drive ROS production. Recent studies indicating that the cytoplasmic domain of RAGE binds to the formin mDia1 provide further support for the critical roles of this pathway in oxidative stress; mDia1 was required for activation of rac1 and NADPH oxidase in primary murine aortic smooth muscle cells treated with RAGE ligand S100B. In vivo, in multiple distinct disease models in animals, RAGE action generates oxidative stress and modulates cellular/tissue fate in range of disorders, such as in myocardial ischemia, atherosclerosis, and aneurysm formation. Blockade or genetic deletion of RAGE was shown to be protective in these settings. Indeed, beyond cardiovascular disease, evidence is accruing in human subjects linking levels of RAGE ligands and soluble RAGE to oxidative stress in disorders such as doxorubicin toxicity, acetaminophen toxicity, neurodegeneration, hyperlipidemia, diabetes, preeclampsia, rheumatoid arthritis and pulmonary fibrosis. Blockade of RAGE signal transduction may be a key strategy for the prevention of the deleterious consequences of oxidative stress, particularly in chronic disease. |
topic |
receptor for advanced glycation endproduct non-enzymatic glycation inflammation redox signaling |
url |
http://www.mdpi.com/1422-0067/14/10/19891 |
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