Abstract

Although hyperhomocysteinemia is an independent risk factor for myocardial infarction and stroke, the mechanistic link between homocysteine (Hcy) and arteriosclerosis is unknown. We have proposed hypomethylation as a specific mechanism by which Hcy inhibits endothelial regeneration that leads to cardiovascular disease [11. Our plan in the ongoing research """"""""Inhibition of Endothelial Growth by Homocysteine"""""""" (ROl-I-IL67033) is to elucidate the molecular mechanisms by which Hcy inhibits endothelial cell (EC) growth and to evaluate its role in a hyperhomocysteinemic mouse model. EC growth is a key step of vasculogenesis and angiogenesis. The growth inhibitory effect of Hcy on EC growth suggests a role in the development of atherosclerosis and vasculogenesis. The basic hypothesis of this proposed project is that Hcy inhibits EC differentiation and vascular development. This is based on our previous finding that Hcy selectively inhibits EC growth, and our new observation that there is a decrease in vascularization in hyperhomocysteinemic mice. This hypothesis is supported by studies from others showing that Hcy inhibits angiogenesis in vitro and in vivo. We plan to investigate the effect of Hcy on EC differentiation and vasculogenesis using human embryonic stem (ES) cells, and to test the role of the targeting molecules during this process.
In Aim 1, we will determine the effect of Hcy on EC differentiation by embryoid body (EB) formation using human ES cell line 1-19 clone (NIH Code: WA09) from WiCell Research Inst (Madison, WI), which has been validated for EC differentiation.
In Aim 2, we will assess the status and the role of Ras demethylation and cyclin A inhibition in Hcy signaling in EC derived from human ES cells. We anticipate that our studies will advance the body of knowledge that will establish a mechanistic connection between Hcy and impaired human vasculogenesis, and will help in achieving our primary goal in the ongoing research, which is to understand the effect of Hcy in human endothelial biology. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL067033-02S1
Application #
6743936
Study Section
Special Emphasis Panel (ZRG1-CDF-5 (50))
Program Officer
Ershow, Abby
Project Start
2001-04-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$66,918
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

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
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, 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
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
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
Nelson, Jun; Wu, Yi; Jiang, Xiaohua et al. (2015) Hyperhomocysteinemia suppresses bone marrow CD34+/VEGF receptor 2+ cells and inhibits progenitor cell mobilization and homing to injured vasculature-a role of ?1-integrin in progenitor cell migration and adhesion. FASEB J 29:3085-99
Cheng, Zhongjian; Jiang, Xiaohua; Pansuria, Meghana et al. (2015) Hyperhomocysteinemia and hyperglycemia induce and potentiate endothelial dysfunction via ?-calpain activation. Diabetes 64:947-59
Liu, Suxuan; Xiong, Xinyu; Zhao, Xianxian et al. (2015) F-BAR family proteins, emerging regulators for cell membrane dynamic changes-from structure to human diseases. J Hematol Oncol 8:47
Tan, Hongmei; Shi, Chengwei; Jiang, Xiaohua et al. (2014) Hyperhomocysteinemia promotes vascular remodeling in vein graph in mice. Front Biosci (Landmark Ed) 19:958-66

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