Radical roles for RAGE in the pathogenesis of oxidative stress in cardiovascular diseases and beyond

Abstract

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.

Figure 1

AGE-RAGE, oxidative stress and amplification loops linked to the pathogenesis of chronic disease. We propose that generation and accumulation of AGEs (red triangles) may be an important triggering event in a diverse array of stimuli, such as hyperglycemia, natural aging, inflammatory mechanisms and oxidative stress (such as via the myeloperoxidase pathway), and ischemia-reperfusion. Once AGEs achieve degrees of modification/concentrations sufficient to bind to and activate RAGE, RAGE signaling, at least in part through the interaction of its cytoplasmic domain with the formin, mDia1, results in activation of NADPH oxidase and the generation of ROS. Such ROS, via mitochondrial amplification, may generate even further ROS. One consequence of increased NADPH oxidase- and mitochondrial ROS generation is the consumption of antioxidant defenses. Together with RAGE-dependent suppression of Glo1, AGE formation and accumulation is sustained and amplified. Once set in motion, AGEs may stimulate recruitment of RAGE-expressing inflammatory cells which, when activated, may result in the release of non-AGE RAGE ligands, such as S100/calgranulins and HMGB1 (blue triangles). Such non-AGE + AGE ligands of RAGE may stimulate yet an additional amplification loop of RAGE activation, that is, cellular stress and activation of gene programs that augur tissue damage and reduced activation of repair mechanisms. We posit that such cellular stimulation mediated by AGE-RAGE and the indicated amplification loops contribute to the pathogenesis of the complications of diabetes, cardiovascular disease, autoimmunity and innate aging. Blocking AGE formation, RAGE signaling and the indicated amplification loops may be essential for the prevention of these chronic disorders.