S100A12 Mediates Aortic Wall Remodeling and Aortic Aneurysm

Abstract

Rationale: S100A12 is a small calcium binding protein that is a ligand of RAGE (receptor for advanced glycation end products). RAGE has been extensively implicated in inflammatory states such as atherosclerosis, but the role of S100A12 as its ligand is less clear. Objective: To test the role of S100A12 in vascular inflammation, we generated and analyzed mice expressing human S100A12 in vascular smooth muscle under control of the smooth muscle 22␣ promoter because S100A12 is not present in mice. Methods and Results: Transgenic mice displayed pathological vascular remodeling with aberrant thickening of the aortic media, disarray of elastic fibers, and increased collagen deposition, together with increased latent matrix metalloproteinase-2 protein and reduction in smooth muscle stress fibers leading to a progressive dilatation of the aorta. In primary aortic smooth muscle cell cultures, we found that S100A12 mediates increased interleukin-6 production, activation of transforming growth factor ␤ pathways and increased metabolic activity with enhanced oxidative stress. To correlate our findings to human aortic aneurysmal disease, we examined S100A12 expression in aortic tissue from patients with thoracic aortic aneurysm and found increased S100A12 expression in vascular smooth muscle cells. Conclusions: S100A12 expression is sufficient to activate pathogenic pathways through the modulation of oxidative stress, inflammation and vascular remodeling in vivo. (Circ Res. 2010;106:145-154.)

Effect of Circulating Soluble Receptor for Advanced Glycation End Products (sRAGE) and the Proinflammatory RAGE Ligand (EN-RAGE, S100A12) on Mortality in Hemodialysis Patients

“…These data are compatible with the hypothesis that high sRAGE may act as a vasculoprotective factor in this population, whereas S100A12 may be deleterious as a decoy of the AGE-RAGE activation of the inflammatory response. Additionally, S100A12 related to IL-6 in our study, in agreement with an animal report in transgenic mice overexpressing human S100A12 that demonstrated the mediation of S100A12 in the process of IL-6 production and aortic wall remodeling (33). Several clinical studies have consistently shown the association between circulating S100A12 and atherosclerosis or CVD risk (30,34).…”

“…However, the predictive value on CVD outcome still remained, leading us to speculate that S100A12 may lead to atherogenesis and mortality by yet uncharacterized non-proinflammatory mechanisms. In accordance, a recent report by Hofman et al (33) demonstrates that S100A12 reduces vascular smooth muscle cell proliferation and increases cytosolic H 2 O 2 production via NADPH oxidase system. Theoretically, possible therapeutic strategies targeting S100A12 may raise considerable interest.…”

IL-22 is induced by S100/calgranulin and impairs cholesterol efflux in macrophages by downregulating ABCG1

“…We measured the level of other cytokines in the plasma of hBAC/S100 mice because S100A12A was previously shown to induce IL-6, TNF ␣ , and other cytokines ( 19,31,34 ). IL-6 was increased 2-fold in hS100/calgranulin transgenic mice, while TNF ␣ and IL-1 ␤ levels were similar to WT mice ( Fig.…”

Calgranulins May Contribute Vascular Protection In Atherogenesis

“…60 Studies with mice overexpressing human S100A12 suggest that it mediates aortic wall remodeling by promoting inflammation and oxidative stress, partly via ligation of RAGE and TGF-β activation. 49 Vascular SMC overexpressing S100A12 have higher metabolic activity and mitochondrial ROS production than in wild-type mice. Backcrosses of S100A12 transgenic mice with hyperlipidemic ApoE-null mice develop somewhat larger plaques, with larger calcified areas than do wild-type/ApoE -/-mice, although S100A12 alone was insufficient to promote vascular changes.…”

“…48 S100A12 has been found in macrophages 42 and smooth muscle cells (SMC) in ruptured plaque and localized to the medial layer at sites of degeneration and dissection of thoracic aneurysms. 49 Functions of Calgranulins in CVD The elevated calgranulin levels in lesions, and within the circulation of patients with atherosclerosis have implicated them in disease pathogenesis, although precise roles are still being defined. Proposed functions of S100A8 and S100A9 were recently reviewed 50, 51 and are largely based on their extracellular roles in leukocyte adhesion and recruitment, and proposed cytotoxic effects.…”