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Thrombosis and atherosclerosis
1Center for Molecular and Vascular Biology, University of Leuven, Belgium. paul.holvoet@med.kuleuven.ac.be
Insights
Atherosclerosis initiation involves monocyte targeting and inflammation. Key adhesion molecules and platelet interactions contribute to lesion development and plaque rupture, highlighting inflammation
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Atherosclerosis begins with monocyte recruitment to inflamed endothelium.
- Inflammation and endothelial injury are critical early steps.
- Adhesion molecules play a significant role in leukocyte targeting.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying atherosclerosis initiation.
- To investigate the roles of inflammatory mediators and cell adhesion in atherogenesis.
- To explore the contribution of platelets and lipoproteins to atherosclerotic plaque development.
Main Methods:
- Analysis of serum levels of intercellular adhesion molecule-1.
- Investigation of E-selectin gene polymorphisms.
- Assessment of interleukin-8 expression in cholesterol-loaded macrophages.
- Evaluation of endothelium-platelet and platelet-matrix interactions.
- Study of oxidized low-density lipoprotein (LDL) effects on macrophages and endothelium.
Main Results:
- Increased intercellular adhesion molecule-1 in ischemic heart disease patients.
- E-selectin gene polymorphisms linked to accelerated atherosclerosis in young patients.
- Cholesterol loading induces interleukin-8, linking foam cells to leukocyte adhesion.
- Hypercholesterolemia enhances endothelium-platelet interactions via von Willebrand factor.
- Activated platelets promote leukocyte homing and contribute to LDL oxidation and smooth muscle cell proliferation.
- Oxidized LDL induces tissue factor, impairing anticoagulant pathways.
Conclusions:
- Inflammation, mediated by adhesion molecules and cytokines, is central to atherosclerosis.
- Platelet activation and interactions are crucial in leukocyte recruitment and plaque progression.
- Lipoprotein oxidation and impaired anticoagulant mechanisms exacerbate atherosclerotic lesion development.
Abstract:
The initial step in atherosclerosis is the rapid targeting of monocytes to the sites of inflammation and endothelial injury. Serum levels of intercellular adhesion molecule-1 were found to be increased in ischaemic heart disease patients and polymorphisms in the E-selectin gene were associated with accelerated atherosclerosis in young (age < 40 years) patients, further suggesting a role of inflammation in atherosclerosis. Cholesterol loading in macrophages was found to induce interleukin-8 expression, suggesting an association between foam cell formation and beta 2-integrin-dependent adhesion of leukocytes. Enhanced endothelium-platelet interaction induced by hypercholesterolaemia is mediated by von Willebrand factor, whereas platelet adhesion to subendothelial matrix is mediated by fibulin-fibrinogen complexes. Activated platelets mediate the homing of leukocytes by interaction with the subendothelial matrix under shear stresses that do not allow neutrophil adhesion. They may also contribute to the oxidative modification of LDL, provide a source of lipids for foam cell generation and contribute to smooth muscle cell proliferation. Oxidized LDL induces tissue factor in macrophages that also provide sites for fibrin polymerization and decreases the anticoagulant activity of endothelium by interfering with thrombomodulin expression and inactivating tissue factor pathway inhibitor. Intravascular fibrinolysis induced by tissue-type plasminogen activator or urokinase may contribute to the initiation of atherosclerosis by inducing P-selectin and platelet activating factor as well as to plaque rupture, either directly or indirectly, by activating metalloproteinases. Plasminogen activator inhibitor-1 inhibits smooth muscle cell migration and, in the presence of vitronectin, promotes the clearance of thrombin by LDL receptor-related protein at sites of endothelial injury.