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| Mechanism behind platelet function and potentially fatal blood clot formation identified |
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September 2007
Researchers at Cleveland Clinic have identified the mechanism that accounts for platelet hyperresponsiveness during abnormal blood cholesterol levels, a major risk factor for heart attacks and strokes.
In their work, the researchers investigated the mechanisms of how platelets become hyperreactive during hyperlipidaemia. It has long been recognised that a high-fat diet and abnormal lipid levels can alter platelet function, increasing chances of creating potentially lethal blood clots causing heart attack and stroke. However, the mechanisms responsible for enhanced platelet reactivity remain unclear.
Proatherosclerotic lipid abnormalities are associated with both enhanced oxidant stress and the generation of biologically active oxidised lipids, including potential ligands for the scavenger receptor CD36, a major platelet glycoprotein.
Using human clinical studies and mouse models, researchers led by Eugene A. Podrez, M.D., Ph.D., of Cleveland Clinic's Lerner Research Institute, Department of Molecular Cardiology, now demonstrate that genetic deletion of Cd36 protects mice from hyperlipidaemia-associated enhanced platelet reactivity and the accompanying prothrombotic phenotype.
The researchers found that structurally defined oxidised choline glycerophospholipids that serve as high-affinity ligands for CD36 were markedly increased in the plasma of hyperlipidaemic mice and humans with low HDL levels, and were able to bind platelets via CD36 and, at pathophysiological levels, promoted platelet activation via CD36.
"By identifying mechanisms responsible for the hyperactivity of platelets during hyperlipidaemia, new therapies may be developed to prevent inappropriate platelet activation and reduce the risk of adverse cardiovascular events," Dr Podrez said.
"Life-threatening cardiovascular events, such as heart attack and stroke, occur when plaque or fatty deposits rupture and trigger the formation of blood clots inside blood vessels," said Stanley Hazen, M.D., Ph.D., Section Head of Preventive Cardiology and co-investigator on the study.
"Thus, interactions of platelet CD36 with specific endogenous oxidised lipids play a crucial role in the well-known clinical associations between dyslipidaemia, oxidant stress and a prothrombotic phenotype," they concluded.
Reference:
Nature Medicine 2007; 13 (9): 1086–1095.
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