Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts

Abstract

Accelerated atherosclerosis in patients with diabetes is a major cause of their morbidity and mortality, and it is unresponsive to therapy aimed at restoring relative euglycemia. In hyperglycemia, nonenzymatic glycation and oxidation of proteins and lipids results in the accumulation of irreversibly formed advanced glycation endproducts. These advanced glycation endproducts engage their receptor in cells of the blood vessel wall, thereby activating mechanisms linked to the development of vascular lesions. We report here a model of accelerated and advanced atherosclerosis in diabetic mice deficient for apolipoprotein E. Treatment of these mice with the soluble extracellular domain of the receptor for advanced glycation endproducts completely suppressed diabetic atherosclerosis in a glycemia- and lipid-independent manner. These findings indicate interaction between the advanced glycation endproducts and their receptor is involved in the development of accelerated atherosclerosis in diabetes, and identify this receptor as a new therapeutic target in diabetic macrovascular disease.

Articular chondrocytes express the receptor for advanced glycation end products: Potential role in osteoarthritis

“…It is not clear if this is an artifact or if it is indicative of RAGE binding to the surface of cartilage. The latter could occur, since secreted RAGE has been found in serum (25) and, so, may be present in synovial fluid as well, although this has not been examined. Immunostaining was stronger and more extensive in cartilage from OA joints, with more cells staining in the deeper zones and with some matrix staining also noted ( Figure 1F).…”

Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications

“…Besides, smooth muscle cells and nerves in the vessel wall showed constitutively high levels of RAGE expression that were unchanged with ageing or by the presence of vascular disease [83]. Consistent with a pathogenic role for ligand×RAGE interaction in nondiabetic atherosclerosis, sRAGE reduced atherosclerotic lesions and inflammation in normoglycaemic Apoe −/− mice without affecting plasma cholesterol and triacylglycerol levels [84][85][86][87]. Wild-type mice treated with sRAGE and Rage −/− mice also showed significantly reduced neointima expansion in femoral artery denudation-induced arterial injury models, whereas protection conferred by sRAGE was more prominent than that due to RAGE deletion [40,88].…”

RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response

“…In parallel with reduced expression of RAGE and S100/calgranulins in sRAGE-treated joints, clinical indices of inflammation 18 were consistently lower in mice treated with sRAGE vs phosphate-buffered saline (PBS) or murine serum albumin (Figure 2a). In addition, histologic scoring 19 revealed marked decreases in synovial hyperplasia/hypertrophy in the joints of sRAGE-treated mice (Figure 2b).…”

“…Three weeks later, mice were challenged with bovine type II collagen (day 22). The contribution of RAGE to the pathogenesis of arthritis was studied by treating animals with soluble (s) RAGE, 1,18 the extracellular ligandbinding domain of the receptor, 100 g per day, beginning 3 weeks after initial immunization (day 22). In previous studies, blockade of RAGE at this dose effected the greatest decrease in the proinflammatory phenotype in a murine model of delayed-type hypersensitivity.…”