Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL110764-02
Application #
8321485
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
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$508,173
Indirect Cost
$176,034

  Institution

Name
Temple University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122

  Publications

Xu, Keman; Yang, William Y; Nanayakkara, Gayani Kanchana et al. (2018) GATA3, HDAC6, and BCL6 Regulate FOXP3+ Treg Plasticity and Determine Treg Conversion into Either Novel Antigen-Presenting Cell-Like Treg or Th1-Treg. Front Immunol 9:45
Wang, Yuchen; Tian, Hong; Cai, Wenzhi et al. (2018) Tracking hematopoietic precursor division ex vivo in real time. Stem Cell Res Ther 9:16
Fang, Pu; Li, Xinyuan; Dai, Jin et al. (2018) Immune cell subset differentiation and tissue inflammation. J Hematol Oncol 11:97
Sun, Yu; Johnson, Candice; Zhou, Jun et al. (2018) Uremic toxins are conditional danger- or homeostasis-associated molecular patterns. Front Biosci (Landmark Ed) 23:348-387
Li, Xinyuan; Wang, Luqiao; Fang, Pu et al. (2018) Lysophospholipids induce innate immune transdifferentiation of endothelial cells, resulting in prolonged endothelial activation. J Biol Chem 293:11033-11045
Li, Xinyuan; Shao, Ying; Sha, Xiaojin et al. (2018) IL-35 (Interleukin-35) Suppresses Endothelial Cell Activation by Inhibiting Mitochondrial Reactive Oxygen Species-Mediated Site-Specific Acetylation of H3K14 (Histone 3 Lysine 14). Arterioscler Thromb Vasc Biol 38:599-609
Cueto, Ramon; Zhang, Lixiao; Shan, Hui Min et al. (2018) Identification of homocysteine-suppressive mitochondrial ETC complex genes and tissue expression profile - Novel hypothesis establishment. Redox Biol 17:70-88
Zeng, Huihong; Nanayakkara, Gayani K; Shao, Ying et al. (2018) DNA Checkpoint and Repair Factors Are Nuclear Sensors for Intracellular Organelle Stresses-Inflammations and Cancers Can Have High Genomic Risks. Front Physiol 9:516
Cheng, Zhongjian; Shen, Xinggui; Jiang, Xiaohua et al. (2018) Hyperhomocysteinemia potentiates diabetes-impaired EDHF-induced vascular relaxation: Role of insufficient hydrogen sulfide. Redox Biol 16:215-225
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 :

Showing the most recent 10 out of 41 publications