Atherosclerosis is a chronic inflammatory disease of the arterial vessel wall that progresses from a fatty streak to a fibrofattymatrix and fibrous plaque. Monocyte interactions with the inflamed endothelium, monocyte recruitment to the arterial vesselwall and their subsequent transformation to lipid-enriched foam cells initiate and sustain atherosclerosis. The long-term goal of this research project is to elucidate the mechanisms underlying the regulation of the inflammatory aspects of atherosclerosis so that novel evidence-based approaches can be developed to treat atherosclerosis. The central hypothesis of this proposal is that suppressing adenosine kinase (ADK) inhibits the inflammatory aspects of atherosclerosis and further curbs the formation of atherosclerotic lesions. Adenosine, a purine nucleoside that is elaborated the sites of inflammation, has a central role in regulating the inflammatory response. However, the short half-life and systemic side effects of adenosine or adenosine analogues limit their application. ADK is an intracellular enzyme that catalyzes the phosphorylation of adenosine to AMP. Inhibition of ADK increases the levels of adenosine in the intracellular compartment and causes a subsequent increase in the extracellular compartment. ADK inhibition is efficacious at suppressing many inflammatory diseases in animal models. However, the role of ADK inhibition in atherosclerosis has not been defined. We have recently found the following: (i) an ADK inhibitor suppresses the formation of atherosclerotic lesions in mice; (ii) ADK knockdown in endothelial cells decreases cytokine-induced endothelial activation; and (iii) the deficiency of ADK in myeloid leukocytes reduces the formation of atherosclerotic lesions in mice. The goal of this project is to use tissue- specific ADK-deficient mice to investigate the extent to which ADK deficiency in endothelial cells or monocytes/macrophages contributes to the reduction of inflammatory responses and the suppression of atherosclerosis.
In specific aim 1, we will investigate the effect of endothelial ADK deficiency on the decreased inflammatory adhesiveness of the arterial endothelium and the suppressed formation of atherosclerotic lesions.
In specific aims 2 to 4, we will investigate the effects of monocyte ADK deficiency on the decline of monocyte recruitment to atherosclerotic arteries, macrophage activation and foam cell formation, as well as the growth of advanced atherosclerotic lesions. We will also determine the contribution of the PI3K/Akt and adenosine receptor 2A (A2AR) to the effects of ADK deficiency. These studies will have significant implications for the use of ADK inhibitors as therapeutic agents to prevent and treat atherosclerosis and its complications.

Public Health Relevance

Adenosine kinase (ADK) is a key intracellular molecule in regulating the levels of adenosine in intracellular and further extracellular compartments. This project is designed to use tissue- specific ADK deletion mice to investigate whether and how ADK in endothelial cells and/or monocytes plays a crucial role in the formation of atherosclerotic lesions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL095556-02
Application #
8415996
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
2011-08-08
Project End
2015-11-30
Budget Start
2012-02-06
Budget End
2012-11-30
Support Year
2
Fiscal Year
2011
Total Cost
$332,428
Indirect Cost
Name
Georgia Regents University
Department
Biology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Zhang, Min; Zeng, Xianqiu; Yang, Qiuhua et al. (2018) Ablation of Myeloid ADK (Adenosine Kinase) Epigenetically Suppresses Atherosclerosis in ApoE-/- (Apolipoprotein E Deficient) Mice. Arterioscler Thromb Vasc Biol 38:2780-2792
Pei, Ya; Li, Honggui; Cai, Yuli et al. (2018) Regulation of adipose tissue inflammation by adenosine 2A receptor in obese mice. J Endocrinol 239:365-376
Cai, Yuli; Li, Honggui; Liu, Mengyang et al. (2018) Disruption of adenosine 2A receptor exacerbates NAFLD through increasing inflammatory responses and SREBP1c activity. Hepatology 68:48-61
Xu, Yiming; Wang, Yong; Yan, Siyuan et al. (2017) Regulation of endothelial intracellular adenosine via adenosine kinase epigenetically modulates vascular inflammation. Nat Commun 8:943
Xu, Yiming; Wang, Yong; Yan, Siyuan et al. (2017) Intracellular adenosine regulates epigenetic programming in endothelial cells to promote angiogenesis. EMBO Mol Med 9:1263-1278
Qi, Ting; Chen, Yanming; Li, Honggui et al. (2017) A role for PFKFB3/iPFK2 in metformin suppression of adipocyte inflammatory responses. J Mol Endocrinol 59:49-59
Guo, Xin; Shu, Chang; Li, Honggui et al. (2017) Cyclic GMP-AMP Ameliorates Diet-induced Metabolic Dysregulation and Regulates Proinflammatory Responses Distinctly from STING Activation. Sci Rep 7:6355
Chen, Jiang-Fan; Zhang, Shuya; Zhou, Rong et al. (2017) Adenosine receptors and caffeine in retinopathy of prematurity. Mol Aspects Med 55:118-125
Wang, Yusi; Pati, Paramita; Xu, Yiming et al. (2016) Endotoxin Disrupts Circadian Rhythms in Macrophages via Reactive Oxygen Species. PLoS One 11:e0155075
Chen, Lili; Zhao, Jiajia; Tang, Qingming et al. (2016) PFKFB3 Control of Cancer Growth by Responding to Circadian Clock Outputs. Sci Rep 6:24324

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