Modification of platelet proteins by malondialdehyde: prevention by dicarbonyl scavengers[S]

• Published in: Journal of lipid research 2015-11, Vol.56 (11), p.2196-2205
• Main Authors: Zagol-Ikapite, Irene, Sosa, Iberia R., Oram, Denise, Judd, Audra, Amarnath, Kalyani, Amarnath, Venkataraman, Stec, Donald, Oates, John A., Boutaud, Olivier
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aminosalicylic Acids - pharmacology; Anemia, Sickle Cell - blood; Blood Platelets - drug effects; Blood Platelets - metabolism; Blood Proteins - metabolism; cross-link; cyclooxygenase; Drug Evaluation, Preclinical; Humans; Malondialdehyde - blood; mass spectrometry; metabolic syndrome; Metabolic Syndrome - blood; Middle Aged; nonsteroidal anti-inflammatory drug; Patient-Oriented and Epidemiological Research; Platelet Activation; salicylamine; sickle cell disease; thromboxane synthase
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.P063271

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.