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Review
. 2015 Dec;35(12):2496-507.
doi: 10.1161/ATVBAHA.115.302072. Epub 2015 Oct 29.

S100A12 and the S100/Calgranulins: Emerging Biomarkers for Atherosclerosis and Possibly Therapeutic Targets

Adam Oesterle  1 , Marion A Hofmann Bowman  2
Affiliations
Review

S100A12 and the S100/Calgranulins: Emerging Biomarkers for Atherosclerosis and Possibly Therapeutic Targets

Adam Oesterle et al. Arterioscler Thromb Vasc Biol. 2015 Dec.

Abstract

Atherosclerosis is mediated by local and systematic inflammation. The multiligand receptor for advanced glycation end products (RAGE) has been studied in animals and humans and is an important mediator of inflammation and atherosclerosis. This review focuses on S100/calgranulin proteins (S100A8, S100A9, and S100A12) and their receptor RAGE in mediating vascular inflammation. Mice lack the gene for S100A12, which in humans is located on chromosome 3 between S100A8 and S100A9. Transgenic mice with smooth muscle cell-targeted expression of S100A12 demonstrate increased coronary and aortic calcification, as well as increased plaque vulnerability. Serum S100A12 has recently been shown to predict future cardiovascular events in a longitudinal population study, underscoring a role for S100A12 as a potential biomarker for coronary artery disease. Genetic ablation of S100A9 or RAGE in atherosclerosis-susceptible apolipoprotein E null mice results in reduced atherosclerosis. Importantly, S100A12 and the RAGE axis can be modified pharmacologically. For example, soluble RAGE reduces murine atherosclerosis and vascular inflammation. Additionally, a class of compounds currently in phase III clinical trials for multiple sclerosis and rheumatologic conditions, the quinoline-3-carboxamides, reduce atherosclerotic plaque burden and complexity in transgenic S100A12 apolipoprotein E null mice, but have not been tested with regards to human atherosclerosis. The RAGE axis is an important mediator for inflammation-induced atherosclerosis, and S100A12 has emerged as biomarker for human atherosclerosis. Decreasing inflammation by inhibiting S100/calgranulin-mediated activation of RAGE attenuates murine atherosclerosis, and future studies in patients with coronary artery disease are warranted to confirm S100/RAGE as therapeutic target for atherosclerosis.

Keywords: S100/calgranulins; S100A12; apolipoprotein E; atherosclerosis; coronary artery disease; inflammation.

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Figures

Figure 1
Figure 1. Ligand-mediated activation of the receptor for advanced glycation endproducts (RAGE) mediates inflammation
A) Ligands of RAGE, including advanced glycation endproducts (AGEs), high mobility group protein box 1 (HMGB1), S100/calgranulins, and lysophosphatidic acid (LPA) are released during cell stress and bind to RAGE on monocytes and smooth muscle cells (B) and endothelial cells (C). This activates pathways, leading to the translocation of transcription factor kappa B (NFkB) and increased reactive oxygen species (ROS), which results in a proinflammatory cell phenotype. Endogenous and pharmacological compounds with the ability to bind RAGE-ligands are suggested as possible therapeutic interventions to block activation of RAGE and other targets [modified from reference 3].
Figure 2
Figure 2
Transgenic expression of human S100A12 targeted to smooth muscle accelerates atherosclerotic remodeling with calcification, necrotic core, and elastic fiber degradation in Apolipoprotein (Apo)E null mice (a–c) compared to wild type (WT/ApoE) littermate mice (d–f) and promotes medial calcification in normolipidemic C57BL6/J mice (g,h). Alizarin Red stain for calcium (a,d,g), hematoxylin and eosin stain (b,e) and Verhoeff van Giessen stain for elastic fibers (c,f). L=lumen. Insert in b magnifies osteoblast like cell. [modified from reference 46]
Figure 3
Figure 3. Treatment with ABR-21757 improves features of atherosclerotic plaque morphology (A–J) and reduces vascular inflammation (K–O)
Innominate artery lesions from control S100A12/Apolipoprotein (Apo)E−/− (A–D) and in mice receiving treatment with ABR-215757 (E–H) stained with Masson trichrome (A,E), Alizarin Red S (calcium phosphate in red, B,F), Verhoeff-Van Gieson (elastic fibers in black, C,G), and Hematoxin & Eosin (D,H). Original magnification, 10×, scale bare, 10 μm. Quantification of lesion characteristics for necrotic area (I) and Alizarin Red stained plaque area (J). K–M: Protein level for S100/calgranulin and RAGE in aortic tissue lysates and mRNA (N–O) in aortic tissue in WT/ApoE−/− and S100A12/ApoE−/− mice after 5 weeks of ABR-215757 or vehicle treatment. [modified from reference .]
Figure 4
Figure 4
Cumulative incidence curves for first, second, and third tertile of serum S100A12 (EN-RAGE) in relation to incidence of coronary artery disease adjusting for competing noncoronary heart disease death ≤10 years of follow up. EN-RAGE = extra-cellular newly identified receptor for advanced glycation endprodcuts binding protein. [Reproduced with permission from 83]
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