Editorial Vascular Calcification It ’ s All the RAGE !

Macrovascular calcification increasingly afflicts our aging and dysmetabolic population.1 Once considered only a passive process of dead and dying cells, data from multiple laboratories worldwide have converged to reveal that vascular calcification is in great part an actively regulated form of matrix mineral metabolism.2 A uniquely horrendous situation arises in end-stage renal disease.3 Antecedent vasculopathy from diabetes, dyslipidemia, or hypertension interacts with dialysis-modulated uremia—a fluctuating hyperphosphatemic and hyperphosphatemic milieu that increases vascular smooth muscle cell (VSMC) apoptosis, overwhelms defenses against soft tissue mineralization, and promotes low-grade panvascular inflammation.3,4 Elegant genetic studies by Cecil and Terkeltaub,5 coupled with the enlightening work of Festing et al6 and Li et al7 have highlighted the important role of pyrophosphate and phosphate metabolism in the pathobiology of arterial calcification. In addition, oxidative stress signals (reactive oxygen species [ROS]) elaborated in response to key inflammatory cytokines— namely, interleukin 6,8 interleukin 1 ,9 and tumor necrosis factor10,11—have been shown to participate in vascular activation of the osteochondrogenic gene programs characteristic of bone formation.12 Only recently, however, has signaling via the receptor for advanced glycosylation end products (RAGE) been implicated as a critical contributor to both ROS-regulated13 and pyrophosphate-regulated5 vascular calcification. RAGE is an immunoglobulin superfamily member, initially identified by Yan et al as an endothelial cell surface receptor for glycated proteins that accumulate with hyperglycemia.14 Although membrane-bound RAGE promotes nuclear factorB15 and ROS16 signaling, soluble RAGE (sRAGE) functions as a dominant-negative “faux receptor” for RAGE-activating ligands14 (Figure). Indeed, sRAGE levels are reduced in patients with calcific aortic stenosis,17 suggesting that unchecked RAGE-dependent inflammation may contribute to valve calcium load.18 As immediately germane to the pathobiology of diabetic arterial calcification,19 carboxymethyl lysine and other advanced glycation end-products bind RAGE and sRAGE as ligands.15 However, RAGE functions as a crucial signal transducer for HMGB1 and S100A/calgranulin family members, proteins released with cell necrosis and leukocyte activation, respectively.14,20 Seminal studies from Hofmann Bowman et al first identified expression of S100A12—a human RAGE ligand—in aortic aneurysms.21 Furthermore, they showed that transgenic expression of human S100A12 in VSMCs promotes dilating aortic matrix remodeling in mice.21 Although elastinolysis and oxidative stress—stimuli for vascular calcification22—were concomitantly upregulated by the S100A12 transgene, the impact on arteriosclerotic calcium accrual was not previously addressed.21