Hyperhomocycteinemia (HHcy) is an independent risk factor for cardiovascular disease in the general population and associated with vascular diseases in diabetic patients{Hackam, 2003 #101;Schnyder, 2002 #102;Schnyder, 2002 #102}. When diabetes is compounded HHcy, cardiovascular mortality is about 2-fold greater than in those without HHcy. We have obtained substantial preliminary data showing that the combination of HHcy and Hyperglycemia (HHcy/HG) accelerated the development of atherosclerotic lesion, increased monocyte (MC)/macrophage (M) in the lesion, elevated inflammatory subsets of MC and M (Ly6Cmiddle+high MC and M1 M) in peripheral tissues. It is known that inflammatory MC and M contribute to vascular and systemic inflammation. In this proposal, we will examine the role and mechanism of Hcy in MC/M differentiation and in vascular inflammation, a key status determining atherosclerosis and cardiovascular disease, in combinatory diseases of HHcy and diabetes. Our central hypothesis is that HHcy promotes inflammatory MC/M differentiation via DNA hypomethylation thereby accelerating atherogenesis in diabetes. We will test our hypothesis by using the following three Aims:
Aim 1 will examine the effect of HHcy on inflammatory MC/M differentiation and vascular diseases in diabetes animals.
Aim 2 will access mechanisms contributing to HHcy-induced MC differentiation in T2DM.
Aim 3 will identify the role of DNA hypomethylation in mediating HHcy- induced MC differentiation and test a novel DNA methylation therapy in preventing inflammatory MC/M differentiation and vascular diseases in diabetes animals. Success of this project will lead to the development of novel therapeutics for HHcy- related diabetic cardiovascular disease.

Public Health Relevance

Diabetes is a common metabolic disease affecting >8.5% of the US population, about 25.8 million children and adults. When diabetes are compounded with increased plasma homocysteine levels, termed as hyperhomocycteinemia (HHcy), cardiovascular mortality is about 2-folds greater than in those without HHcy. However, the mechanisms underlying increased CVD risk in compound HHcy and diabetic disorders are unknown. The proposed studies will examine the contribution and mechanism of HHcy and diabetes in vascular inflammation, a key status determining atherosclerosis and cardiovascular disease. Success of this study would characterize monocyte and macrophage differentiation in HHcy-accelerated atherosclerosis in diabetes and lead to the development of new therapeutics for the treatment of CVD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK104116-02
Application #
9130162
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Abraham, Kristin M
Project Start
2015-08-20
Project End
2020-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Temple University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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
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
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
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
Virtue, Anthony; Johnson, Candice; Lopez-PastraƱa, Jahaira et al. (2017) MicroRNA-155 Deficiency Leads to Decreased Atherosclerosis, Increased White Adipose Tissue Obesity, and Non-alcoholic Fatty Liver Disease: A NOVEL MOUSE MODEL OF OBESITY PARADOX. J Biol Chem 292:1267-1287
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 :
Shao, Ying; Nanayakkara, Gayani; Cheng, Jiali et al. (2017) Lysophospholipids and Their Receptors Serve as Conditional DAMPs and DAMP Receptors in Tissue Oxidative and Inflammatory Injury. Antioxid Redox Signal :

Showing the most recent 10 out of 20 publications