title: Elevated release of sCD40L from platelets of diabetic patients by thrombin, glucose and advanced glycation end products.
abstract: The pro-inflammatory CD40/CD40L dyad participates in atherogenesis. Plasma levels of the soluble ligand (sCD40L) predict cardiovascular events and are elevated in diabetic patients. This study compared CD40/CD40L surface expression on platelets and T lymphocytes of diabetic and control subjects, and tested whether glucose and advanced glycation end products (AGEs) stimulate sCD40L release. Constitutive and inducible surface expression of CD40/CD40L on platelets or T lymphocytes did not differ between diabetic patients (n = 9) and controls (n = 13). Platelets from diabetic patients contained higher intracellular CD40L than controls (p < 0.05) and thrombin stimulated greater platelet sCD40L release in diabetic patients (15.11 +/- 16.77 ng/ml) compared to controls (3.64 +/- 2.03 ng/ml; p < 0.05). Glucose and AGEs induced platelet sCD40L release and CD40L expression in mouse megakaryocytes. This study demonstrates elevated CD40L content and inducible release from platelets of diabetic patients, and identifies glucose and AGEs as potential triggers of expression and release accounting for the elevated sCD40L plasma levels in these patients.
authors.affiliation: Donald W Reynolds Cardiovascular Clinical Research Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nerea
authors.initials: N
authors.lastname: Varo
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nuzzo
authors.forename: Joseph
authors.initials: J
authors.lastname: Italiano
authors.forename: Alessandro
authors.initials: A
authors.lastname: Doria
authors.forename: Uwe
authors.initials: U
authors.lastname: Schönbeck
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology; D001792:Blood Platelets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000032:analysis; D023201:CD40 Ligand / Q000032:analysis / Q000097:blood* / Q000494:pharmacology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005947:Glucose / Q000494:pharmacology / Q000502:physiology; D017127:Glycation End Products, Advanced / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology / Q000502:physiology
chemical_list: D019013:CD40 Antigens; D018946:Chemokine CCL5; D017127:Glycation End Products, Advanced; D019007:P-Selectin; D010982:Platelet-Derived Growth Factor; D011994:Recombinant Proteins; D023201:CD40 Ligand; D013917:Thrombin; D005947:Glucose