ATP binding cassette transporter A1 (ABCA1) is involved in regulation of intracellular lipid trafficking and export of cholesterol from cells to high density lipoproteins. ABCA1 defects cause Tangier disease, a disorder characterized by absence of high density lipoprotein and thrombocytopenia. In the present study we have demonstrated that ABCA1 is expressed in human platelets and that fibrinogen binding and CD62 surface expression in response to collagen and low concentrations of thrombin, but not to ADP, are defective in platelets from Tangier patients and ABCA1-deficient animals. The expression of platelet membrane receptors such as GPVI, alpha2beta1 integrin, and GPIIb/IIIa, the collagen-induced changes in phosphatidylserine and cholesterol distribution, and the collagen-induced signal transduction examined by phosphorylation of LAT and p72syk and by intracellular Ca2+ mobilization were unaltered in Tangier platelets. The electron microscopy of Tangier platelets revealed reduced numbers of dense bodies and the presence of giant granules typically encountered in platelets from Chediak-Higashi syndrome. Further studies demonstrated impaired release of dense body content in platelets from Tangier patients and ABCA1-deficient animals. In addition, Tangier platelets were characterized by defective surface exposure of dense body and lysosomal markers (CD63, LAMP-1, LAMP-2, CD68) during collagen- and thrombin-induced stimulation and by abnormally high lysosomal pH. We conclude that intact ABCA1 function is necessary for proper maturation of dense bodies in platelets. The impaired release of the content of dense bodies may explain the defective activation of Tangier platelets by collagen and low concentrations of thrombin, but not by ADP.
Pubmed ID: 15163665 RIS Download
Mesh terms: ATP Binding Cassette Transporter 1 | ATP-Binding Cassette Transporters | Adenosine Diphosphate | Aged | Animals | Antigens, CD | Antigens, Differentiation, Myelomonocytic | Blood Platelets | Cell Adhesion Molecules | Collagen | Cytoplasmic Granules | Fibrinogen | Humans | Hydrogen-Ion Concentration | Lysosome-Associated Membrane Glycoproteins | Lysosomes | Male | Mice | Mice, Inbred C57BL | Mice, Knockout | Microscopy, Electron | Middle Aged | Phosphatidylserines | Platelet Activation | Platelet Membrane Glycoproteins | Tangier Disease | Tetraspanin 30 | Thrombin
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.