Modification of platelet proteins by malondialdehyde: prevention by dicarbonyl scavengers |
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Authors: | Irene Zagol-Ikapite Iberia R. Sosa Denise Oram Audra Judd Kalyani Amarnath Venkataraman Amarnath Donald Stec John A. Oates Olivier Boutaud |
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Affiliation: | 4. Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN;2. Department of Pharmacology, Vanderbilt University, Nashville, TN |
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Abstract: | The thromboxane synthase converts prostaglandin H2 to thromboxane A2 and malondialdehyde (MDA) in approximately equimolar amounts. A reactive dicarbonyl, MDA forms covalent adducts of amino groups, including the ε-amine of lysine, but the importance of this reaction in platelets was unknown. Utilizing a novel LC/MS/MS method for analysis of one of the MDA adducts, the dilysyl-MDA cross-link, we demonstrated that dilysyl-MDA cross-links in human platelets are formed following platelet activation via the cyclooxygenase (COX)-1/thromboxane synthase pathway. Salicylamine and analogs of salicylamine were shown to react with MDA preferentially, thereby preventing formation of lysine adducts. Dilysyl-MDA cross-links were measured in two diseases known to be associated with increased platelet activation. Levels of platelet dilysyl-MDA cross-links were increased by 2-fold in metabolic syndrome relative to healthy subjects, and by 1.9-fold in sickle cell disease (SCD). In patients with SCD, the reduction of platelet dilysyl-MDA cross-links following administration of nonsteroidal anti-inflammatory drug provided evidence that MDA modifications of platelet proteins in this disease are derived from the COX pathway. In summary, MDA adducts of platelet proteins that cross-link lysines are formed on platelet activation and are increased in diseases associated with platelet activation. These protein modifications can be prevented by salicylamine-related scavengers. |
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Keywords: | mass spectrometry thromboxane synthase cross-link metabolic syndrome sickle cell disease nonsteroidal anti-inflammatory drug cyclooxygenase salicylamine |
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