Hyperhomocysteinemia is a modifiable, independent risk factor for cardiovascular disease, cognitive dysfunction, complications of pregnancy, and osteoporosis. Homocysteine-induced endothelial cell dysfunction may link this diverse group of pathologies. Our research has focused on: 1) the vascular biochemistry of homocysteine; 2) the mechanism of homocysteine transport in cultured human aortic endothelial cells; and, 3) the molecular targeting of protein cysteine residues by homocysteine. Thiol-disulfide exchange accounts for the forms of homocysteine in circulation. Cysteine transporters mediate homocysteine import in the vascular endothelium. Evidence is provided that links homocysteine targeting to vascular cell dysfunction. The long-term objectives are to understand the mechanism of homocysteine-accelerated atherogenesis and to develop improved interventional strategies that will lower plasma total homocysteine in high-risk subjects and in subjects who are refractory to conventional therapy (e.g., end-stage renal disease). Our central hypotheses are: 1) homocysteine is a mediator of early atherogenesis but becomes a marker in advanced atherosclerosis (we call this the """"""""mediator ?>? marker hypothesis"""""""" of hyperhomocysteinemia); 2) monocyte chemoattractant protein 1 and other pro-inflammatory cytokines are induced by homocysteine in early atherogenesis by a mechanism involving the activation of NF-kB; 3) the fundamental mechanism underlying homocysteine causality is molecular targeting; and, 4) homocysteine-lowering by primary intervention will reduce mortality and morbidity associated with hyperhomocysteinemia.
Our specific aims are: 1) to study the mechanism of protein homocysteinylation and functional consequences; 2) to study the transport and metabolism of homocysteine and its disulfide congeners in vascular cells; and, 3) to identify intracellular proteins (e.g., metallothionein) targeted by homocysteine and how loss of function of targeted proteins leads to vascular cell dysfunction. The program to fortify the American diet with folic acid, completed in January, 1998, has had a profound effect on reducing the incidence of hyperhomocysteinemia, neural tube defects and, possibly, mortality due to stroke and heart attack. Additional public health benefits are likely by gaining a better understanding of homocysteine transport, metabolism and the adverse effects of homocysteine on our circulatory system. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL052234-14
Application #
7435295
Study Section
Special Emphasis Panel (ZRG1-EMNR-J (03))
Program Officer
Ershow, Abby
Project Start
1994-12-01
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
14
Fiscal Year
2008
Total Cost
$375,049
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Hannibal, Luciana; DiBello, Patricia M; Jacobsen, Donald W (2013) Proteomics of vitamin B12 processing. Clin Chem Lab Med 51:477-88
Metes-Kosik, Nicole; Luptak, Ivan; Dibello, Patricia M et al. (2012) Both selenium deficiency and modest selenium supplementation lead to myocardial fibrosis in mice via effects on redox-methylation balance. Mol Nutr Food Res 56:1812-24
Moreira, Edward S; Brasch, Nicola E; Yun, June (2011) Vitamin B12 protects against superoxide-induced cell injury in human aortic endothelial cells. Free Radic Biol Med 51:876-83
Hannibal, Luciana; DiBello, Patricia M; Yu, Michelle et al. (2011) The MMACHC proteome: hallmarks of functional cobalamin deficiency in humans. Mol Genet Metab 103:226-39
Tsitsiou, Eleni; Sibley, Colin P; D'Souza, Stephen W et al. (2011) Homocysteine is transported by the microvillous plasma membrane of human placenta. J Inherit Metab Dis 34:57-65
Al-Hashimi, Ali A; Caldwell, Jennifer; Gonzalez-Gronow, Mario et al. (2010) Binding of anti-GRP78 autoantibodies to cell surface GRP78 increases tissue factor procoagulant activity via the release of calcium from endoplasmic reticulum stores. J Biol Chem 285:28912-23
Quadros, Edward V; Lai, Shao-Chiang; Nakayama, Yasumi et al. (2010) Positive newborn screen for methylmalonic aciduria identifies the first mutation in TCblR/CD320, the gene for cellular uptake of transcobalamin-bound vitamin B(12). Hum Mutat 31:924-9
DiBello, Patricia M; Dayal, Sanjana; Kaveti, Suma et al. (2010) The nutrigenetics of hyperhomocysteinemia: quantitative proteomics reveals differences in the methionine cycle enzymes of gene-induced versus diet-induced hyperhomocysteinemia. Mol Cell Proteomics 9:471-85
Hannibal, Luciana; Smith, Clyde A; Jacobsen, Donald W (2010) The X-ray crystal structure of glutathionylcobalamin revealed. Inorg Chem 49:9921-7
Chen, Xiaocong; Sebastian, Becky M; Tang, Hui et al. (2009) Taurine supplementation prevents ethanol-induced decrease in serum adiponectin and reduces hepatic steatosis in rats. Hepatology 49:1554-62

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