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 immuno-suppressive cells, inhibit vascular inflammation. Tregs, but not other T cells, are decreased in homocysteine (Hcy) elevated-apolipoprotein E deficient (ApoE-/-) mice. Consequently, HHcy- promoted 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 pro-apoptotic 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 (co-investigator)'s laboratory that HHcy promotes vascular inflammation and atherosclerosis in cystathionine ?-synthase (Cbs)-/-/ApoE-/- double knock-out (KO) mice. Wang's team was also the first to show that HHcy leads to accumulation of SAH (S-adenosylhomocysteine, a potent inhibitor of methyltransferases) and DNA hypomethylation. In addition, our laboratory has a long- standing 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 HHcy-induced 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 HHcy-induced Treg apoptosis and enhance Treg suppression of HHcy-induced vascular inflammation.
Elevated level of plasma homocysteine (Hcy), termed hyperhomocysteinemia (HHcy), is an independent risk factor for human coronary heart disease (CHD) and stroke. Thus, HHcy-induced 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.
|Li, Xinyuan; Fang, Pu; Yang, William Y et al. (2017) 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 95:247-252|
|Li, Xinyuan; Fang, Pu; Yang, William Y et al. (2017) IL-35, as a newly proposed homeostasis-associated molecular pattern, plays three major functions including anti-inflammatory initiator, effector, and blocker in cardiovascular diseases. Cytokine :|
|Dai, Jin; Fang, Pu; Saredy, Jason et al. (2017) Metabolism-associated danger signal-induced immune response and reverse immune checkpoint-activated CD40+ monocyte differentiation. J Hematol Oncol 10:141|
|Xu, Yanjie; Xia, Jixiang; Liu, Suxuan et al. (2017) Endocytosis and membrane receptor internalization: implication of F-BAR protein Carom. Front Biosci (Landmark Ed) 22:1439-1457|
|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|
|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|
|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, Ping; Wei, Xin; Zhang, Jian et al. (2016) Antithrombotic Effects of Nur77 and Nor1 Are Mediated Through Upregulating Thrombomodulin Expression in Endothelial Cells. Arterioscler Thromb Vasc Biol 36:361-9|
|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|
|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|
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