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1.  Beneficial effects of quinoline-3-carboxamide (ABR-215757) on atherosclerotic plaque morphology in S100A12 transgenic ApoE null mice 
Atherosclerosis  2013;228(1):69-79.
There is an emerging widespread interest in the role of damage-associated molecular pattern molecules (DAMP) S100A8, S100A9 and S100A12 in cardiovascular and other diseases. In this study we tested the efficacy of ABR-215757, a S100 protein binding immuno-modulatory compound to stabilize atherosclerosis in transgenic ApoE null mice that express the human pro-inflammatory S100A12 protein within the smooth muscle cell (SM22α-S100A12).
Twelve-week old S100A12 transgenic/ApoE-/- and WT/ApoE-/- mice were treated with ABR-21575 for 5 weeks and were analyzed 4 month later.
Surface plasmon resonance analysis demonstrated that S100A12 interacts with ABR-215757 in a zinc dependent manner in vitro. In vivo, ABR-215757 administration reduced features of advanced plaque morphology resulting in smaller necrotic cores, diminished intimal and medial vascular calcification, and reduced amount of infiltrating inflammatory cells. ABR-215757 normalized aortic expression of RAGE protein and normalized experimentally-induced delayed hypersensitivity. The effect of ABR-215757 was more prominent in ApoE-/- mice expressing S100A12 than in ApoE-/- animals lacking expression of human S100A12 protein.
Our data suggest that S100A12 is important for progression of atherosclerosis and can be targeted by the small molecule ABR-215757. The specific binding of quinoline-3-carboxamides to S100A12 attenuates S100A12-mediated features of accelerated murine atherosclerosis.
PMCID: PMC3640742  PMID: 23497784
atherosclerosis; S100 proteins; RAGE; Quinoline-3-carboxamides
2.  S100A12 expression in thoracic aortic aneurysm is associated with increased risk of dissection and perioperative complications 
To determine the relevance of S100A12 expression to human thoracic aortic aneurysms (TAA) and type A dissection (TAAD) and to study mechanisms of S100A12 mediated dysfunction of aortic smooth muscle cells.
Transgenic expression of pro-inflammatory S100A12 protein in murine aortic smooth muscle causes thoracic aneurysm in genetically modified mice.
Immunohistochemistry of aortic tissue (n=50) for S100A12, myeloperoxidase and caspase 3 was examined, and S100A12 mediated pathways were studied in cultured primary aortic smooth muscle cells.
We found S100A12 protein expressed in all cases of acute TAAD, and in approximately 25% of clinically stable TAA cases. S100A12 tissue expression was associated with increased length of stay in patients undergoing elective surgical repair for TAA despite similar preoperative risk as determined by EuroSCORE. Reduction of S100A12 expression in human aortic smooth muscle cells using shRNA attenuates gene and protein expression of many inflammatory and apoptosis regulating factors. Moreover, genetic ablation of the receptor for S100A12, RAGE, in murine aortic smooth muscle cells abolished cytokine- augmented activation of caspase 3 and smooth muscle cell apoptosis in S100A12-expressing cells.
S100A12 is enriched in human thoracic aortic aneurysms and dissections. Reduction of S100A12 or genetic ablation of its cell surface receptor RAGE in aortic smooth muscle resulted in decreased activation of caspase 3 and in reduced apoptosis. By establishing a link between S100A12 expression and apoptosis of aortic smooth muscle cells, this study identifies novel S100A12 signaling pathways and indicates that S100A12 may be a useful molecular marker and possible target for treatment for human aortic diseases.
PMCID: PMC3422448  PMID: 22818064
Thoracic aortic aneurysm and dissection; S100 proteins; RAGE; aortic smooth muscle cells; cell death
3.  S100A12 in Vascular Smooth Muscle Accelerates Vascular Calcification in Apolipoprotein E–Null Mice by Activating an Osteogenic Gene Regulatory Program 
The proinflammatory cytokine S100A12 is associated with coronary atherosclerotic plaque rupture. We previously generated transgenic mice with vascular smooth muscle–targeted expression of human S100A12 and found that these mice developed aortic aneurysmal dilation of the thoracic aorta. In the current study, we tested the hypothesis that S100A12 expressed in vascular smooth muscle in atherosclerosis-prone apolipoprotein E (ApoE)–null mice would accelerate atherosclerosis.
Methods and Results
ApoE-null mice with or without the S100A12 transgene were analyzed. We found a 1.4-fold increase in atherosclerotic plaque size and more specifically a large increase in calcified plaque area (45% versus 7% of innominate artery plaques and 18% versus 10% of aortic root plaques) in S100A12/ApoE-null mice compared with wild-type/ApoE-null littermates. Expression of bone morphogenic protein and other osteoblastic genes was increased in aorta and cultured vascular smooth muscle, and importantly, these changes in gene expression preceded the development of vascular calcification in S100A12/ApoE-null mice. Accelerated atherosclerosis and vascular calcification were mediated, at least in part, by oxidative stress because inhibition of NADPH oxidase attenuated S100A12-mediated osteogenesis in cultured vascular smooth muscle cells. S100A12 transgenic mice in the wild-type background (ApoE+/+) showed minimal vascular calcification, suggesting that S100A12 requires a proinflammatory/proatherosclerotic environment to induce osteoblastic differentiation and vascular calcification.
Vascular smooth muscle S100A12 accelerates atherosclerosis and augments atherosclerosis-triggered osteogenesis, reminiscent of features associated with plaque instability.
PMCID: PMC3364048  PMID: 20966394
calcification; coronary artery disease; genetically altered mice; vascular biology
4.  Vascular Remodeling and Arterial Calcification Are Directly Mediated by S100A12 (EN-RAGE) in Chronic Kidney Disease 
American Journal of Nephrology  2011;33(3):250-259.
The proinflammatory cytokine S100A12 (also known as EN-RAGE) is associated with cardiovascular morbidity and mortality in hemodialysis patients. In the cur- rent study, we tested the hypothesis that S100A12 expressed in vascular smooth muscle in nonatherosclerosis-prone C57BL/6J mice on normal rodent chow diet, but exposed to the metabolic changes of chronic kidney disease (CKD), would develop vascular disease resembling that observed in patients with CKD.
CKD was induced in S100A12 transgenic mice and wild-type littermate mice not expressing human S100A12 by surgical ligation of the ureters. The aorta was analyzed after 7 weeks of elevated BUN (blood urea nitrogen), and cultured aortic smooth muscle cells were studied.
We found enhanced vascular medial calcification in S100A12tg mice subjected to CKD. Vascular calcification was mediated, at least in part, by activation of the receptor for S100A12, RAGE (receptor for advanced glycation endproducts), and by enhanced oxidative stress, since inhibition of NADPH-oxidase Nox1 and limited access of S100A12 to RAGE attenuated the calcification and gene expression of osteoblastic genes in cultured vascular smooth muscle cells.
S100A12 augments CKD-triggered osteogenesis in murine vasculature, reminiscent of features associated with enhanced vascular calcification in patients with chronic and end-stage kidney disease.
PMCID: PMC3064943  PMID: 21372560
Chronic kidney disease; Blood urea nitrogen; Receptor for advanced glycation endproducts

Results 1-4 (4)