Rupture of atherosclerotic plaques in the carotid artery results in neurological problems. Inflammatory cytokines in the plaque induce apoptosis of vascular smooth muscle cells (VSMCs), thus thinning the fibrous cap and resulting in plaque destabilization and rupture. During the initial funding cycle, we made novel observations that IGF-1 is more potent in inducing the survival of VSMCs in carotid endarterectomy tissues of asymptomatic than symptomatic patients. Also, atheroma-associated cytokines decrease IGF-1-induced survival and proliferation of VSMCs. In our follow-up studies we observed specific differences in the profile of dendritic cells (DCs), T-regulatory cells, and NPY and NPY receptors in symptomatic (unstable) and asymptomatic (stable) plaques. Also, stronger immunoreactivity of Foxp3, IL-10 and CD25 with preponderance of CD4? T cells in carotid plaques of asymptomatic than symptomatic patients. IGF-1 increased mRNA transcripts of NPY-Y2 and NPY-Y5 receptors in asymptomatic but not in symptomatic plaque SMCs. These novel findings suggest a cell-mediated immune response in carotid plaques which is regulated by NPY. Our central hypothesis is that the inflammation in the carotid plaque is modulated by interaction of NPY with DCs and T cells leading to increased inflammation and apoptosis of VSMCs in carotid plaques of symptomatic patients with carotid stenosis, and that atheroma-associated cytokines modulate NPY receptors and their function in VSMCs of carotid plaques.
In Aim 1, we will examine the phenotypes of dendritic cells and the effect of NPY, in the presence and absence of IGF-1, on the cell surface expression of co-stimulatory molecules in DCs in the carotid plaques of symptomatic and asymptomatic patients with carotid stenosis.
In Aim 2, we will examine the phenotype of T-regulatory cells (inducible CD4? T-regs and naturally-occurring CD4???? T-regs) and the effect of NPY, in the presence and absence of IGF-1, on the cell surface expression of the receptors for co-stimulatory molecules (PD-1, CTLA- 4) in T-regs from the carotid plaques of symptomatic and asymptomatic patients with carotid stenosis. We will also determine the effect of NPY, in the presence and absence of atheroma-associated cytokines, on the differentiation of naive T cells into T-regulatory cells.
In Aim 3, we will examine the effect of NPY, in the presence and absence of inflammatory cytokines, on the survival and apoptosis of VSMCs isolated from the carotid plaques of symptomatic and asymptomatic patients with carotid stenosis. The long-term goal of this study is to determine the cellular and molecular mechanisms responsible for the instability and rupture of carotid plaques in patients with carotid stenosis. Such investigations would provide unique insights to the pathophysiologic process of neurological diseases associated with the rupture of atherosclerotic plaques and the means to prevent the disease in patients with carotid stenosis.

Public Health Relevance

Many patients with blockade of their neck artery develop neurological symptoms including transient ischemic attack or stroke. This is primarily due to breaking off the atherosclerotic plaque in the neck artery. In this project experiments are proposed to examine the underlying cellular and molecular mechanisms of the plaque rupture. Information obtained from this study should provide an opportunity to formulate superior therapeutic approaches in the prevention of stroke.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073349-08
Application #
8197534
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Liu, Lijuan
Project Start
2003-04-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
8
Fiscal Year
2012
Total Cost
$321,874
Indirect Cost
$99,124
Name
Creighton University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
053309332
City
Omaha
State
NE
Country
United States
Zip Code
68178
Aggarwal, Ankita; Agrawal, Devendra K (2014) Importins and exportins regulating allergic immune responses. Mediators Inflamm 2014:476357
Makinde, Toluwalope O; Steininger, Robert; Agrawal, Devendra K (2013) NPY and NPY receptors in airway structural and inflammatory cells in allergic asthma. Exp Mol Pathol 94:45-50
Jia, Guanghong; Aggarwal, Anshu; Tyndall, Steve H et al. (2011) Tumor necrosis factor-ýý regulates p27 kip expression and apoptosis in smooth muscle cells of human carotid plaques via forkhead transcription factor O1. Exp Mol Pathol 90:1-8
Pankajakshan, Divya; Jia, Guanghong; Pipinos, Iraklis et al. (2011) Neuropeptide Y receptors in carotid plaques of symptomatic and asymptomatic patients: effect of inflammatory cytokines. Exp Mol Pathol 90:280-6
Aggarwal, Anshu; Hunter 3rd, William J; Aggarwal, Himanshu et al. (2010) Expression of leukemia/lymphoma-related factor (LRF/POKEMON) in human breast carcinoma and other cancers. Exp Mol Pathol 89:140-8
Jia, Guanghong; Cheng, Gang; Gangahar, Deepak M et al. (2008) Involvement of connexin 43 in angiotensin II-induced migration and proliferation of saphenous vein smooth muscle cells via the MAPK-AP-1 signaling pathway. J Mol Cell Cardiol 44:882-90
Bharadwaj, Arpita S; Agrawal, Devendra K (2007) Flt3 ligand generates morphologically distinct semimature dendritic cells in ovalbumin-sensitized mice. Exp Mol Pathol 83:17-24
Moran, Edward P; Agrawal, Devendra K (2007) Increased expression of inhibitor of apoptosis proteins in atherosclerotic plaques of symptomatic patients with carotid stenosis. Exp Mol Pathol 83:11-6
Agrawal, Anshu; Murphy, Richard F; Agrawal, Devendra K (2007) DNA methylation in breast and colorectal cancers. Mod Pathol 20:711-21
Pandey, Saumya; Murphy, Richard F; Agrawal, Devendra K (2007) Recent advances in the immunobiology of ceramide. Exp Mol Pathol 82:298-309

Showing the most recent 10 out of 40 publications