Abstract

Atherosclerosis and its complications are the most common causes of morbidity and mortality. These vascular diseases result from adhesive and signaling interactions among leukocytes, platelets and the vessel wall cells. These cellular interactions are mediated by adhesion molecules, including P, E, L-selectin, P-selectin glycoprotein ligand 1 (PSGL-1), CD43, CD44, integrin CD18, VLA-4, and others. The cellular interactions mediated by these molecules broadly participate in various events in atherosclerosis. To obtain optimal activities, molecules including PSGL-1, CD43 and CD44 need to be modified by the addition of branched O-glycans to their protein structures. These reactions are catalyzed by core 2 1-6-N- glucosaminyltransferase-l (C2GlcNAcT-l), which is a Golgi enzyme in leukocytes. This project is designed to investigate whether C2GlcNAcT-l is crucial for cellular interactions involved in the development of atherosclerosis and its complications.
In aim 1, we will investigate the rote of C2GlcNAcT-l in the interactions of mononuclear cells with atherosclerotic arteries.
In aim 2, we will investigate the role of C2GlcNAcT-l in the contribution of activated platelets to atherosclerosis.
In aim 3, we will investigate the role of C2GlcNAcT-l in the development, progression and regression of atherosclerotic lesions. We will also evaluate the influence of C2GlcNAcT-l in the stability of atherosclerotic lesions.
In aim 4, we will investigate the role of C2GlcNAcT-l in the interactions of leukocytes and platelets with injured arteries and in the formation of arterial neointima using an established mouse carotid artery wire injury model. These studies will have significant implications for the inhibition of leukocyte C2GlcNAcT-l in the prevention and treatment of atherosclerosis and its complications.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080569-04
Application #
7634399
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
2006-07-01
Project End
2011-12-31
Budget Start
2009-07-01
Budget End
2011-12-31
Support Year
4
Fiscal Year
2009
Total Cost
$362,911
Indirect Cost

  Institution

Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455

  Publications

Wei, Shujian; Wang, Huan; Zhang, Guoying et al. (2013) Platelet I?B kinase-? deficiency increases mouse arterial neointima formation via delayed glycoprotein Ib? shedding. Arterioscler Thromb Vasc Biol 33:241-8
Zhang, Weiyu; Zhang, Xianling; Wang, Huan et al. (2012) AMP-activated protein kinase ?1 protects against diet-induced insulin resistance and obesity. Diabetes 61:3114-25
Guo, Xin; Li, Honggui; Xu, Hang et al. (2012) Palmitoleate induces hepatic steatosis but suppresses liver inflammatory response in mice. PLoS One 7:e39286
Huo, Yuqing; Guo, Xin; Li, Honggui et al. (2012) Targeted overexpression of inducible 6-phosphofructo-2-kinase in adipose tissue increases fat deposition but protects against diet-induced insulin resistance and inflammatory responses. J Biol Chem 287:21492-500
Zhang, Weiyu; Wang, Jianguo; Wang, Huan et al. (2010) Acadesine inhibits tissue factor induction and thrombus formation by activating the phosphoinositide 3-kinase/Akt signaling pathway. Arterioscler Thromb Vasc Biol 30:1000-6
Wang, Huan; Zhang, Weiyu; Tang, Rong et al. (2010) Adenosine receptor A2A deficiency in leukocytes increases arterial neointima formation in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 30:915-22
Huo, Yuqing; Guo, Xin; Li, Honggui et al. (2010) Disruption of inducible 6-phosphofructo-2-kinase ameliorates diet-induced adiposity but exacerbates systemic insulin resistance and adipose tissue inflammatory response. J Biol Chem 285:3713-21
Guo, Xin; Xu, Kefeng; Zhang, Jifeng et al. (2010) Involvement of inducible 6-phosphofructo-2-kinase in the anti-diabetic effect of peroxisome proliferator-activated receptor gamma activation in mice. J Biol Chem 285:23711-20
Ashino, Takashi; Sudhahar, Varadarajan; Urao, Norifumi et al. (2010) Unexpected role of the copper transporter ATP7A in PDGF-induced vascular smooth muscle cell migration. Circ Res 107:787-99
Wang, Huan; Tang, Rong; Zhang, Weiyu et al. (2009) Core2 1-6-N-glucosaminyltransferase-I is crucial for the formation of atherosclerotic lesions in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 29:180-7

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