The overall objective of new application is to determine the role and mechanism of NADPH-related oxidative stress in Hyperhomocysteinemia (HHcy)-caused monocyte differentiation and endothelial dysfunction. The hypothesis to be tested in this proposal is that HHcy causes SAH accumulation, resulting in hypomethylative epigenetic modification on NADHP oxidase gene, leading to NADPH oxidase-related oxidative stress and inflammatory MC differentiation, contributing to vascular dysfunction. This project will study this hypothesis utilizing three linked specific aims.
In Aim 1, they will characterize MC differentiation/adhesion, and vascular function/inflammation in HHcy mice.
In Aim 2, they will examine the role and mechanism of NADPH oxidase activation and epigenetic modification in Hcy-induced MC differentiation in mouse primary splenocytes.
In Aim 3, they will define the role of HHcy, SAH accumulation, DNA hypomethylation, and NADPH oxidase activation in inflammatory MC differentiation and vascular dysfunction in Tg-hCBS Cbs-/- mice. It is believed that completion of the specific aims of this proposal may provide important insights into the role of Hcy in CVD, and identify the underline mechanism.

Public Health Relevance

Increased plasma homocysteine (Hcy) level is an independent risk factor for cardiovascular diseases (CVD). However, the underlying mechanism is largely unknown. This project will illustrate mechanism by which how Hcy causes vessel wall inflammation and impair vascular function, both are early events of cardiovascular disease. We anticipate this study will identify biomarker and novel therapeutic target of cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL110764-03
Application #
8476266
Study Section
Special Emphasis Panel (ZRG1-VH-D (02))
Program Officer
Charette, Marc F
Project Start
2011-08-18
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$483,780
Indirect Cost
$167,584
Name
Temple University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Xie, Liping; Feng, Haihua; Li, Sha et al. (2016) SIRT3 Mediates the Antioxidant Effect of Hydrogen Sulfide in Endothelial Cells. Antioxid Redox Signal 24:329-43
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
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
Lopez-Pastrana, Jahaira; Ferrer, Lucas M; Li, Ya-Feng et al. (2015) Inhibition of Caspase-1 Activation in Endothelial Cells Improves Angiogenesis: A NOVEL THERAPEUTIC POTENTIAL FOR ISCHEMIA. J Biol Chem 290:17485-94
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
Li, Ya-Feng; Ren, Li-Na; Guo, Geng et al. (2015) Endothelial progenitor cells in ischemic stroke: an exploration from hypothesis to therapy. J Hematol Oncol 8:33
Monroy, M Alexandra; Fang, Jianhua; Li, Shan et al. (2015) Chronic kidney disease alters vascular smooth muscle cell phenotype. Front Biosci (Landmark Ed) 20:784-95
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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