PI Siess

Klinische Pathochemie - Atherothrombose: Mechanismen und Hemmung

Clinical Pathobiochemistry - Atherothrombosis: Mechanisms & Inhibition

 

Myocardial infarction and ischaemic stroke are leading causes of morbidity and mortality. The trigger for ca. 70% of acute cardiac ischaemic events is the rupture of vulnerable, lipid rich atherosclerotic plaques, leading to the exposure of thrombogenic plaque material tocirculating blood. Subsequent platelet activation and fibrin formation can lead to occlusive thrombosis, often with fatal consequences. Importantly, atherosclerotic plaques are more thrombogenic than the intima of healthy arteries. It should be therefore possible to inhibit acute atherothrombosis without impairing physiological haemostasis. Present antithrombotic drugs target, however, physiological coagulation factors and platelet activation mechanisms thereby increasing the risk of bleeding. In addition, own studies have shown that plaque induced platelet thrombus formation is not efficiently inhibited by currently used platelet inhibitors (P2Y12 receptor antagonists, aspirin).

The long-term goal of our investigations is to understand the mechanisms of atherothrombosis and to inhibit these specifically without interfering with physiological hemostatic mechanisms.Upon plaque rupture, platelets in circulating blood get exposed to molecules of the ruptured cap and the lipid-rich core. Our previous studies have identified two platelet-activating plaque components and their platelet receptors. Diverse type I and III collagenous structures in the fibrous cap induce platelet adhesion, secretion and aggregation in blood, under static and arterial flow conditions in blood, by activating glycoprotein VI (GPVI) on the platelet surface. Lysophosphatidic acid (LPA), present in the lipid core, mediates shape change of isolated platelets through activation of the LPA5 receptor, but its importance for platelet activation inwhole blood remains to be defined. Plaque tissue factor is involved only in the second step of thrombus formation, i.e. in clotting, but not in the first, platelet activation, after exposure of blood to atherosclerotic plaques. Importantly, blocking platelet GPVI, but not plaque tissue factor inhibited plaque-induced thrombus formation under arterial flow. Beside of the positive identification of thrombogenic plaque components and platelet receptors involved, others have been excluded. Prostaglandin E2, proposed to be a thrombogenicplaque component based on studies in mice, is not relevant in human plaques. Also the platelet serotonin receptor 5-HT2A does not play a role in plaque-induced platelet thrombus formation.

One of our future research aims is directed towards the understanding the architecture, molecular recognition and thrombogenicity of plaque collagens. In contrast to collagens of connective tissue, plaque collagens undergo a high turnover of synthesis and degradation,and they are surrounded by lipids and other matrix proteins accumulating in atherosclerotic plaques. Plaque collagens might bind specific lipids and matrix proteins modifying their thrombogenic properties. The other aim is to understand the regulation of platelet reactivity towards atherosclerotic plaques in healthy persons and cardiovascular patients. High platelet reactivity towards atherosclerotic plaques might predispose patients to exaggerated thrombosis after plaque rupture with the known fatal consequences.

 

Principal Investigator:

Prof. Dr. med. Wolfgang Siess

 

Group members:

Suman Dwivedi

Janina Jamasbi

Kathrin von Oheimb

Nada Vukorepa

 
 
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Direktor: Prof. Dr. med. Christian Weber

Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten (IPEK)

 

Pettenkoferstraße 8a & 9

80336 München

 

Tel.: 089-4400-54351

Fax: 089-4400-54352

Mail: Kreislaufinstitut@med.uni-muenchen.de

 

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