Role of AGEs-RAGE System in Cardiovascular Disease
Kei Fukami, Sho-ichi Yamagishi and Seiya Okuda
Affiliation: Division of Nephrology Department of Medicine, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka 830-0011 Japan.
Keywords: RAGE, AGEs, cardiovascular disease, oxidative stress, HMGB-1.
Advanced glycation end products (AGEs) are a heterogenous group of molecules formed during a non-enzymatic reaction between
proteins and sugar residues. Recently, AGEs and their receptor (receptor for AGEs; RAGE) play a central role in the pathogenesis
of cardiovascular disease (CVD), which accounts for disability and high mortality rate in patients with diabetes. AGEs initiate diabetic
micro- and macrovascular complications through the structural modification and functional alteration of the extracellular matrix proteins
as well as intracellular signaling molecules. Engagement of RAGEs with AGEs elicits intracellular reactive oxygen species (ROS) generation
and subsequently activates mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling, followed by
production of several inflammatory and/or profibrotic factors such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion
molecule-1 (ICAM-1), plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattractant protein-1 (MCP-1), thereby being
involved in the progression of atherosclerosis. Administration of soluble form of RAGE (sRAGE) could work as a decoy receptor for
AGEs and might inhibit the binding of AGEs to RAGE, preventing the development and progression of atherosclerosis in animal models.
Furthermore, AGEs/high mobility group box-1 (HMGB-1)-RAGE interaction is involved in heart failure, abdominal aortic aneurysm
(AAA) and vascular calcification as well. Thus, blockade of the AGEs/HMGB-1-RAGE system may be a promising therapeutic target for
preventing diabetes- and/or age-related CVD. We review here the pathological role of the AGEs/HMGB-1-RAGE system in various
types of CVD.
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