Lesions and neointima that forms following arterial injury are two of the major arterial pathologies in atherosclerosis. These two arterial pathologies are initiated by the recruitment of leukocytes to the arterial vessel walls. The long-term goal of this research is to determine the role of neutrophils in the genesis of arterial diseases. The central hypothesis of this proposal is that neutrophil recruitment to arterial vessel walls is required for the contribution of neutrophils to the development of arterial diseases. In contrast to the well-documented effect of mononuclear cells on the development of arterial diseases, especially spontaneous lesions, the involvement of neutrophils in these arterial diseases is disputable. However, one recent study has reported increased atherosclerosis in mice with a high neutrophil count and decreased atherosclerosis in mice treated with a neutrophil depletion antibody. Although that study points to an important role of neutrophils in atherosclerosis, the approaches it used alter neutrophil homeostasis, and it thus fails to establish a direct link between neutrophil recruitment to the arterial vessel wall and the development of arterial diseases under normal leukocyte homeostasis. Leukocyte recruitment to the arterial vessel wall is initiated by leukocyte tethering and rolling;the latter are mediated by leukocyte selectin ligands [PSGL-1 (ligand for P-selectin) and ligands for E- and L-selectin]. Glycosylation of selectin ligands is crucial for the binding of selectin ligands to the selectins. Core2 1-6-N- glucosaminyltransferase-I (C2GlcNAcT-I) is one of the enzymes that mediate the glycosylation of selectin ligands. Our previous studies have shown that knockout of C2GlcNAcT-I almost completely eliminates leukocyte recruitment to arterial vessel walls and suppresses the formation of spontaneous and neointimal lesions in mice. We have recently generated neutrophil-specific Cre transgenic mice, mice in which the expression of Cre recombinase and EGFP are driven by the regulatory region of the myeloperoxidase (MPO) gene (MPO-Cre mice). By breeding these MPO-Cre mice with floxed C2GlcNAcT-I mice, we have generated mice with C2GlcNAcT-I deficiency specifically in neutrophils. ApoE-/- mice lacking C2GlcNAcT-I specifically in neutrophils (Neu-C2GlcNAcT-I-/-/apoE-/- mice) were also generated. We have found that neutrophils in these mice fail to interact with the endothelium. The goal of this project is to use these mice to investigate the effect of neutrophil recruitment to arterial vessel walls on the formation of spontaneous atherosclerotic lesions and neointimal lesions. Specifically, in two arterial disease models we will examine whether neutrophil C2GlcNAcT- I deficiency affects the recruitment of monocytes and/or platelets to the arterial vessel wall, endothelial regeneration, the formation of spontaneous lesions and arterial neointima following arterial injury in apoE-/- mice. These studies will provide evidence that inhibition of neutrophil recruitment to arteries is a viable approach to the prevention and treatment of arterial diseases.

Public Health Relevance

Results from the proposed research will demonstrate whether neutrophil recruitment to the arterial vessel wall is required for the contribution of neutrophils to the development of arterial diseases. The successful completion of this project will provide evidence for the inhibition of neutrophil homing to arterial vessel walls as one of the approaches for the prevention and treatment of arterial diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL108922-03
Application #
8313874
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
2011-08-08
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
3
Fiscal Year
2013
Total Cost
$178,500
Indirect Cost
$59,500
Name
Georgia Regents University
Department
Biology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
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