text: Activation of human platelets by misfolded proteins.
  OBJECTIVE: Protein misfolding diseases result from the deposition of insoluble protein aggregates that often contain fibrils called amyloid. Amyloids are found in Alzheimer disease, atherosclerosis, diabetes mellitus, and systemic amyloidosis, which are diseases where platelet activation might be implicated. METHODS AND RESULTS: We induced amyloid properties in 6 unrelated proteins and found that all induced platelet aggregation in contrast to fresh controls. Amyloid-induced platelet aggregation was independent of thromboxane A2 formation and ADP secretion but enhanced by feedback stimulation through these pathways. Treatments that raised cAMP (iloprost), sequestered Ca2+ (BAPTA-AM) or prevented amyloid-platelet interaction (sRAGE, tissue-type plasminogen activator [tPA]) induced almost complete inhibition. Modulation of the function of CD36 (CD36-/- mice), p38(MAPK) (SB203580), COX-1 (indomethacin), and glycoprotein Ib alpha (Nk-protease, 6D1 antibody) induced approximately 50% inhibition. Interference with fibrinogen binding (RGDS) revealed a major contribution of alphaIIb beta3-independent aggregation (agglutination). CONCLUSIONS: Protein misfolding resulting in the appearance of amyloid induces platelet aggregation. Amyloid activates platelets through 2 pathways: one is through CD36, p38(MAPK), thromboxane A2-mediated induction of aggregation; the other is through glycoprotein Ib alpha-mediated aggregation and agglutination. The platelet stimulating properties of amyloid might explain the enhanced platelet activation observed in many diseases accompanied by the appearance of misfolded proteins with amyloid.
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entities.type: GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-Y GENE-N GENE-Y CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-N GENE-N GENE-N GENE-N CHEMICAL GENE-N CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
entities.text: fibrinogen alphaIIb beta3 amyloid Amyloid CD36 p38 MAPK amyloid glycoprotein Ib alpha Amyloids thromboxane A2 amyloid Amyloid amyloid tissue-type plasminogen activator tPA CD36 p38 MAPK COX-1 glycoprotein Ib alpha thromboxane A2 Nk-protease ADP cAMP iloprost Ca2+ BAPTA-AM SB203580 indomethacin