RESUMO
The expression of the Receptor for Advanced Glycation Endproducts (RAGE) is upregulated at sites of vascular inflammation and plays a crucial role in vessel homeostasis. Soluble RAGE (sRAGE), a truncated soluble form of the receptor, acts as a decoy and prevents the inflammatory response mediated by RAGE activation. sRAGE has recently emerged as a biomarker in several RAGE-mediated vascular disorders, including coronary artery disease, hypertension, diabetic vasculopathy and Kawasaki disease. Given the pivotal role played by RAGE and sRAGE in numerous vascular disorders, there is a growing need to understand how drugs can modulate the RAGE axis in different disease conditions. In this regard, there is evidence to suggest that traditional cardiovascular drugs (statins, thiazolidinediones, ACE-inhibitors, AT-1 receptor antagonists) as well as nutraceuticals (grape seed proanthocyanidin extract) could modulate RAGE expression and circulating sRAGE levels in cardiovascular disease states characterized by enhanced RAGE activation. Additionally, the production of genetically engineered sRAGE may hold promise for targeting the activation of RAGE by proinflammatory ligands in the setting of vascular inflammation. The present review considers current vascular drugs as modulators of the RAGE axis, and highlights future directions in the context of RAGE-directed therapy in cardiovascular disease.
Assuntos
Receptores Imunológicos/agonistas , Receptores Imunológicos/antagonistas & inibidores , Vasculite/tratamento farmacológico , Processamento Alternativo , Animais , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/terapia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/fisiopatologia , Regulação da Expressão Gênica , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Fragmentos de Peptídeos/agonistas , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/uso terapêutico , Fitoterapia , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/uso terapêutico , Processamento de Proteína Pós-Traducional , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/metabolismo , Receptores Imunológicos/uso terapêutico , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/uso terapêutico , Solubilidade , Vasculite/fisiopatologiaRESUMO
Receptor for AGE (RAGE) is a multi-ligand member of the immunoglobulin superfamily of cell surface molecules. Engagement of RAGE by its signal transduction ligands evokes inflammatory cell infiltration and activation in the vessel wall. In diabetes, when fueled by oxidant stress, hyperglycemia, and superimposed stresses such as hyperlipidemia or acute balloon/endothelial denuding arterial injury, the ligand-RAGE axis amplifies vascular stress and accelerates atherosclerosis and neointimal expansion. In this brief synopsis, we review the use of rodent models to test these concepts. Taken together, our findings support the premise that RAGE is an amplification step in vascular inflammation and acceleration of atherosclerosis. Future studies must rigorously test the potential impact of RAGE blockade in human subjects; such trials are on the horizon.