Elevated level of plasma homocysteine (Hcy), termed hyperhomocysteinemia (HHcy), is an independent risk factor for human coronary heart disease (CHD) and stroke. However, the biochemical mechanisms underlying the effects of HHcy in vascular inflammation and atherosclerosis are poorly defined. The majority of immune cells promote inflammation whereas CD4+CD25highFoxp3+ regulatory T cells (Tregs), the most potent immunosuppressive cells, inhibit vascular inflammation. Tregs, but not other T cells, are decreased in homocysteine (Hcy) elevatedapolipoprotein E deficient (ApoE/ ) mice. Consequently, HHcypromoted Treg reduction may weaken immune suppression and accelerate vascular inflammation. The goal of this project is to examine our central hypothesis that HHcy causes the suppression of DNA methylation in Tregs, which leads to upregulation and activation of proapoptotic protein Bax in Tregs and increased Treg apoptosis, and finally contribute to increased vascular inflammation and dysfunction. This project is proposed based on the pioneer findings from Dr. Hong Wang (coinvestigator)? s laboratory that HHcy promotes vascular inflammation and atherosclerosis in cystathionine βsynthase (Cbs)/ / ApoE/ double knockout (KO) mice. Wang?s team was also the first to show that HHcy leads to accumulation of SAH (Sadenosylhomocysteine, a potent inhibitor of methyltransferases) and DNA hypomethylation. In addition, our laboratory has a longstanding interest and publication record in characterizing apoptosis pathways in Tregs and vascular inflammation. Our goal will be pursued through the execution of the following specific aims: (1) Characterize Treg apoptosis in the spleen, bone marrow (BM), peripheral blood (PB), and arteries in HHcy mice (phenotypic studies). (2) Determine the mechanisms underlying HHcyinduced Treg apoptosis and vascular inflammation (mechanistic studies). (3) Determine the mediating role of DNA hypomethylation and the causative role of HHcy on Bax expression in Tregs and Treg apoptosis (therapeutic/inhibitory studies). Success of this project is significant, which may lead to the development of new therapeutic approaches to inhibit HHcyinduced Treg apoptosis and enhance Treg suppression of HHcy-induced vascular inflammation.

Public Health Relevance

Elevated level of plasma homocysteine (Hcy), termed hyperhomocysteinemia (HHcy), is an independent risk factor for human coronary heart disease (CHD) and stroke. Thus, HHcyinduced chronic vascular inflammation is a major public health problem. This proposal is to study a new molecular roadmap of how HHcy induces vascular inflammations. Success of this project will provide new molecular targets for future development of new therapeutics to treat CHD and stroke.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL116917-01S1
Application #
8789814
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Olive, Michelle
Project Start
2014-02-01
Project End
2017-03-31
Budget Start
2014-02-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$16,062
Indirect Cost
$5,896
Name
Temple University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Shao, Ying; Chernaya, Valeria; Johnson, Candice et al. (2016) Metabolic Diseases Downregulate the Majority of Histone Modification Enzymes, Making a Few Upregulated Enzymes Novel Therapeutic Targets--""Sand Out and Gold Stays"". J Cardiovasc Transl Res 9:49-66
Li, Xinyuan; Fang, Pu; Yang, William Y et al. (2016) Mitochondrial ROS, uncoupled from ATP synthesis, determine endothelial activation for both physiological recruitment of patrolling cells and pathological recruitment of inflammatory cells. Can J Physiol Pharmacol :1-6
Mai, Jietang; Nanayakkara, Gayani; Lopez-Pastrana, Jahaira et al. (2016) Interleukin-17A Promotes Aortic Endothelial Cell Activation via Transcriptionally and Post-translationally Activating p38 Mitogen-activated Protein Kinase (MAPK) Pathway. J Biol Chem 291:4939-54
Yang, Jiyeon; Fang, Pu; Yu, Daohai et al. (2016) Chronic Kidney Disease Induces Inflammatory CD40+ Monocyte Differentiation via Homocysteine Elevation and DNA Hypomethylation. Circ Res 119:1226-1241
Liu, Suxuan; Xiong, Xinyu; Thomas, Sam Varghese et al. (2016) Analysis for Carom complex, signaling and function by database mining. Front Biosci (Landmark Ed) 21:856-72
Ferrer, Lucas M; Monroy, Alexandra M; Lopez-Pastrana, Jahaira et al. (2016) Caspase-1 Plays a Critical Role in Accelerating Chronic Kidney Disease-Promoted Neointimal Hyperplasia in the Carotid Artery. J Cardiovasc Transl Res 9:135-44
Xi, Hang; Zhang, Yuling; Xu, Yanjie et al. (2016) Caspase-1 Inflammasome Activation Mediates Homocysteine-Induced Pyrop-Apoptosis in Endothelial Cells. Circ Res 118:1525-39
Sha, Xiaojin; Meng, Shu; Li, Xinyuan et al. (2015) Interleukin-35 Inhibits Endothelial Cell Activation by Suppressing MAPK-AP-1 Pathway. J Biol Chem 290:19307-18
Lopez-Pastrana, Jahaira; Shao, Ying; Chernaya, Valeria et al. (2015) Epigenetic enzymes are the therapeutic targets for CD4(+)CD25(+/high)Foxp3(+) regulatory T cells. Transl Res 165:221-40
Cheng, Zhongjian; Jiang, Xiaohua; Pansuria, Meghana et al. (2015) Hyperhomocysteinemia and hyperglycemia induce and potentiate endothelial dysfunction via μ-calpain activation. Diabetes 64:947-59

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