title: Modification of platelet proteins by malondialdehyde: prevention by dicarbonyl scavengers.
abstract: The thromboxane synthase converts prostaglandin H(2) to thromboxane A(2) 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.
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Irene
authors.initials: I
authors.lastname: Zagol-Ikapite
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Iberia R
authors.initials: IR
authors.lastname: Sosa
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Denise
authors.initials: D
authors.lastname: Oram
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Audra
authors.initials: A
authors.lastname: Judd
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN.
authors.forename: Kalyani
authors.initials: K
authors.lastname: Amarnath
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN.
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Amarnath
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN.
authors.forename: Donald
authors.initials: D
authors.lastname: Stec
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN Department of Pharmacology, Vanderbilt University, Nashville, TN.
authors.forename: John A
authors.initials: JA
authors.lastname: Oates
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN.
authors.forename: Olivier
authors.initials: O
authors.lastname: Boutaud
mesh_terms: D000328:Adult; D000368:Aged; D000636:Aminosalicylic Acids / Q000494:pharmacology*; D000755:Anemia, Sickle Cell / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008315:Malondialdehyde / Q000097:blood*; D024821:Metabolic Syndrome / Q000097:blood; D008875:Middle Aged; D015539:Platelet Activation
chemical_list: D000636:Aminosalicylic Acids; D001798:Blood Proteins; D008315:Malondialdehyde
keywords: cross-link; cyclooxygenase; mass spectrometry; metabolic syndrome; nonsteroidal anti-inflammatory drug; salicylamine; sickle cell disease; thromboxane synthase