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Modulation of annexin II by homocysteine: implications for atherothrombosis
1Department of Pediatrics, Cornell University Medical College, New York, NY 10021, USA.
Abstract:
Recent evidence indicates a potential role for the plasmin/plasminogen activator system in the prevention of atherosclerotic vascular disease. Fibrin deposition is a common histologic feature of the tissues of mice that are genetically deficient in one or more key components of the fibrinolytic system. Cell surface receptors may support fibrinolytic surveillance in both intravascular and extravascular locations by stimulating the efficiency plasmin generation and by protecting plasmin from its inhibitors. In vitro studies suggest that the endothelial cell receptor, annexin II, which independently binds both plasminogen and t-PA, could play a key role in the process. Binding of plasminogen to annexin II is specifically inhibited in the presence of excess concentrations of the atherogenic LDL-like particle Lp(a). Similarly, t-PA binding to annexin II is blocked by homocysteine, a sulfhydryl-containing amino acid that is associated with atherogenesis and that directly derivatizes the t-PA binding domain of annexin II. Elucidation of the precise role of annexin II in fibrinolytic surveillance, however, will await in vivo study.
Insights
The plasmin/plasminogen activator system may prevent atherosclerosis. Cell surface receptors like annexin II are crucial for fibrinolysis, but Lp(a) and homocysteine may impede this process, requiring further in vivo investigation.
Area of Science:
- Biochemistry
- Vascular Biology
- Molecular Medicine
Background:
- Atherosclerotic vascular disease is linked to fibrin deposition.
- The fibrinolytic system, including plasmin/plasminogen activators, is implicated in preventing atherosclerosis.
- Cell surface receptors may enhance fibrinolysis by promoting plasmin generation and inhibiting plasmin degradation.
Purpose of the Study:
- To investigate the role of the plasmin/plasminogen activator system in preventing atherosclerotic vascular disease.
- To explore the function of cell surface receptors, specifically annexin II, in fibrinolytic surveillance.
- To examine the impact of atherogenic factors like Lp(a) and homocysteine on annexin II-mediated fibrinolysis.
Main Methods:
- Review of recent evidence on the plasmin/plasminogen activator system in atherosclerosis.
- Analysis of histologic features in genetically modified mice lacking fibrinolytic components.
- In vitro studies assessing annexin II binding of plasminogen and tissue plasminogen activator (t-PA).
- Investigation of inhibitory effects of Lp(a) and homocysteine on annexin II interactions.
Main Results:
- Genetic deficiency in fibrinolytic components leads to fibrin deposition in mouse tissues.
- Annexin II, an endothelial cell receptor, binds both plasminogen and t-PA.
- Lp(a) inhibits plasminogen binding to annexin II.
- Homocysteine blocks t-PA binding to annexin II and modifies its binding domain.
Conclusions:
- Annexin II may play a key role in endothelial cell-mediated fibrinolytic surveillance.
- Atherogenic factors, Lp(a) and homocysteine, can interfere with annexin II's function in fibrinolysis.
- Further in vivo studies are necessary to fully elucidate annexin II's role in preventing atherosclerotic vascular disease.