I am interested in mechanisms of vascular disturbances related to atherosclerosis, specifically in the contribution of the pro-inflammatory S100/ calgranulins proteins. S100 A12 was identified in human atheromatous vasculature as well as in the coronary plaque of diabetic patients with sudden coronary death suggesting a role in atherosclerosis and plaque destabilization. Increased serum S100A12 concentrations are present in patients with chronic inflammatory diseases including patients with vasculitis such as Kawasaki disease and in diabetic patients. One mechanism by which S100A12 promotes inflammation is by activation of the receptor for Advanced Glycation Endproducts (RAGE), a receptor strongly linked to vascular dysfunction and atherosclerosis. Specifically, I previously showed that RAGE is a central cell surface receptor for S100A12 leading to activation of endothelial cells and macrophages, cells critically involved in sustained inflammation and vascular dysfunction. I propose to test the hypothesis that S100A12 accelerates atherosclerosis by generating two transgenic mouse models with S100A12 expression targeted to the smooth muscle cells by using the SM22-a promoter and targeted to macrophages by using the CD11b promoter. Two models of vascular dysfunction will be studied: First, I will examine vascular response to a model of arterial injury as there is evidence that S100A12 modulates smooth muscle cell proliferation and migration. Second, I will bred the S100A12 transgenic mice with atherosclerosis prone ApoE null mice and assess at various time points. I expect that S100A12 will accelerate the development of atherosclerosis and I will examine if S100A12 mediates these effects in a RAGE-dependent and in RAGEindependent manner. To test this hypothesis, the S100A12 mice will be bred with the RAGE null and RAGE/ApoE double null mice. These experiments will shed light into the mechanism of pro-inflammatory and pro-thrombotic actions of S100A12 and will provide information on whether these proteins may serve as an important cellular target for the development of new drugs to treat atherosclerosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-O (M1))
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Carlson, Drew E
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University of Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Yan, Ling; Bjork, Per; Butuc, Radu et al. (2013) Beneficial effects of quinoline-3-carboxamide (ABR-215757) on atherosclerotic plaque morphology in S100A12 transgenic ApoE nullýýmice. Atherosclerosis 228:69-79
Hofmann Bowman, Marion A; McNally, Elizabeth M (2012) Genetic pathways of vascular calcification. Trends Cardiovasc Med 22:93-8
Chandra, Sonal; Lang, Roberto M; Nicolarsen, Jeremy et al. (2012) Bicuspid aortic valve: inter-racial difference in frequency and aortic dimensions. JACC Cardiovasc Imaging 5:981-9
Camoretti-Mercado, Blanca; Karrar, Eltayeb; Nuñez, Luis et al. (2012) S100A12 and the Airway Smooth Muscle: Beyond Inflammation and Constriction. J Allergy Ther 3:
Das, Deepanjana; Gawdzik, Joseph; Dellefave-Castillo, Lisa et al. (2012) S100A12 expression in thoracic aortic aneurysm is associated with increased risk of dissection and perioperative complications. J Am Coll Cardiol 60:775-85
Hofmann Bowman, M A; Heydemann, A; Gawdzik, J et al. (2011) Transgenic expression of human S100A12 induces structural airway abnormalities and limited lung inflammation in a mouse model of allergic inflammation. Clin Exp Allergy 41:878-89
Hofmann Bowman, Marion A; Gawdzik, Joseph; Bukhari, Usama et al. (2011) S100A12 in vascular smooth muscle accelerates vascular calcification in apolipoprotein E-null mice by activating an osteogenic gene regulatory program. Arterioscler Thromb Vasc Biol 31:337-44
Hofmann Bowman, Marion A; Fedson, Savitri; Schmidt, Ann Marie (2011) Advanced glycation end products in diabetic cardiomyopathy: an alternative hypothesis. J Heart Lung Transplant 30:1303; discussion 1303-4
Gawdzik, Joseph; Mathew, Liby; Kim, Gene et al. (2011) Vascular remodeling and arterial calcification are directly mediated by S100A12 (EN-RAGE) in chronic kidney disease. Am J Nephrol 33:250-9
Hofmann Bowman, Marion A; Schmidt, Ann Marie (2011) S100/calgranulins EN-RAGEing the blood vessels: implications for inflammatory responses and atherosclerosis. Am J Cardiovasc Dis 1:92-100

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