title: Platelet-Derived S100A8/A9 and Cardiovascular Disease in Systemic Lupus Erythematosus.
abstract: Levels of S100A8/A9, a proinflammatory and prothrombotic protein complex, are increased in several diseases, and high levels predispose to cardiovascular disease (CVD). Recently, platelet S100A8/A9 synthesis was described in mice and humans in relation to CVD. The aim of this study was to investigate the role of platelet S100A8/A9 in systemic lupus erythematosus (SLE), a disease with markedly increased cardiovascular morbidity, as well as the exact platelet distribution of the S100A8/A9 proteins.
  
  
  
  The occurrence and distribution of platelet S100A8/A9 protein were detected by enzyme-linked immunosorbent assay, electron microscopy, Western blotting, and flow cytometry in healthy controls (n = 79) and in 2 individual cohorts of SLE patients (n = 148 and n = 318, respectively) and related to cardiovascular morbidity.
  
  
  
  We observed that human platelets expressed S100A8/A9 proteins, and that these were localized in close proximity to intracellular membranes and granules as well as on the cell surface upon activation with physiologic and pathophysiologic stimuli. Interestingly, S100A8/A9 was enriched at sites of membrane interactions, indicating a role of S100A8/A9 in cell-cell communication. S100A8/A9 levels were highly regulated by interferon-α, both in vivo and in vitro. Patients with SLE had increased platelet S100A8/A9 content compared with healthy individuals. Increased levels of platelet S100A8/A9 were associated with CVD, particularly myocardial infarction (odds ratio 4.8, 95% confidence interval 1.5-14.9, P = 0.032 [adjusted for age, sex, and smoking]).
  
  
  
  Platelets contain S100A8/A9 in membrane-enclosed vesicles, enabling rapid cell surface deposition upon activation. Furthermore, platelet S100A8/A9 protein levels were increased in SLE patients, particularly in those with CVD, and may be a future therapeutic target.
authors.affiliation: Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Lood
authors.affiliation: Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Tydén
authors.affiliation: Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Gullstrand
authors.affiliation: Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Jönsen
authors.affiliation: Lund University, Lund, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Källberg
authors.affiliation: Lund University, Lund, Sweden.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.affiliation: Lund University, Lund, Sweden.
authors.forename: Robin
authors.initials: R
authors.lastname: Kahn
authors.affiliation: Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Iva
authors.initials: I
authors.lastname: Gunnarsson
authors.affiliation: Lund University and Active Biotech AB, Lund, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Leanderson
authors.affiliation: Lund University, Lund, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Ivars
authors.affiliation: Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Svenungsson
authors.affiliation: Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Anders A
authors.initials: AA
authors.lastname: Bengtsson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001792:Blood Platelets / Q000378:metabolism; D040501:Calgranulin A / Q000096:biosynthesis / Q000097:blood*; D040502:Calgranulin B / Q000097:blood*; D002318:Cardiovascular Diseases / Q000097:blood* / Q000209:etiology*; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000150:complications*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B