Hyperhomocyst(e)inemia is a known risk factor for atherosclerotic disease and for venous thromboembolism. The disease, homocystinuria, is a rare inherited disease, in which people die in their teens and early twenties from thrombosis involving the heart, brain or lungs. In this disorder there is a defect in an enzyme in an enzyme involved in hte breakdown of homocyst(e)ine, cystathionien /-synthase. First degree relatives of these people also have slightly elevated levels of homocyst(e)ine, but the levels and the effects are not nearly as severe. Studies have shown that homocyt(e)ine results in vessel damage by injuring the endothelial cells that line vessel walls. Homocyst(e)ine has been shown to alter the normal antithrombotic mechanisms of endothelium. It depresses the activation of protein C, induces the expression of tissue factor, inhibits the expression of heparan sulfate and reduces cell surface tissue plasminogen activator activity. Hydrogen peroxide is produced when homocysteine is added to plasma. If there is increased production or a decreased ability to reduce the hydrogen peroxide, oxidant damage occurs. This is thought to be one of the main mechanisms of damage to the endothelium in hyperhomocyst(e)inemia. Hydrogen peroxide has also been shown to increase expression of the transcription factor-kB (NF-kB). NF-kB in turn causes the expression of adhesion molecules, VACM-1, ICAM-1 and tissue factor. Fas-mediated apoptosis (cell death) is also induced by hydrogen peroxide. These mechanisms all contribute to endothelial damage.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
General Clinical Research Centers Program (M01)
Project #
2M01RR000400-32
Application #
6409121
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Project Start
1978-12-01
Project End
2004-11-30
Budget Start
Budget End
Support Year
32
Fiscal Year
2000
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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