LPS stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway1
| Autor: | Zhang, Guoying, Han, Jingyan, Welch, Emily J., Ye, Richard D., Voyno-Yasenetskaya, Tatyana A., Malik, Asrar B., Du, Xiaoping, Li, Zhenyu |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Blood Platelets
Lipopolysaccharides Platelet Aggregation Lipopolysaccharide Receptors Lymphocyte Antigen 96 Thrombin Article Toll-Like Receptor 4 Mice Myeloid Differentiation Factor 88 Cyclic GMP-Dependent Protein Kinases Animals Humans lipids (amino acids peptides and proteins) Cyclic GMP Protein Binding Signal Transduction |
| Popis: | Bacterial lipopolysaccharide (LPS) induces rapid thrombocytopenia, hypotension and sepsis. Although growing evidence suggests that platelet activation plays a critical role in LPS-induced thrombocytopenia and tissue damage, the mechanism of LPS-mediated platelet activation is unclear. Here we show that LPS stimulates platelet secretion of dense and α granules as indicated by ATP release and P-selectin expression, and thus enhances platelet activation induced by low concentrations of platelet agonists. Platelets express components of the LPS receptor-signaling complex, including Toll-like receptor (TLR4), CD14, MD2, and MyD88, and the effect of LPS on platelet activation was abolished by an anti-TLR4 blocking antibody or TLR4 knockout, suggesting that the effect of LPS on platelet aggregation requires the TLR4 pathway. Furthermore, LPS- potentiated thrombin- and collagen-induced platelet aggregation and FeCl3-induced thrombus formation were abolished in MyD88 knockout mice. LPS also induced cGMP elevation, and the stimulatory effect of LPS on platelet aggregation was abolished by inhibitors of nitric oxide synthase (NOS) and the cGMP-dependent protein kinase (PKG). LPS-induced cGMP elevation was inhibited by an anti-TLR4 antibody or by TLR4 deficiency, suggesting that activation of the cGMP/PKG pathway by LPS involves the TLR4 pathway. Taken together, our data indicate that LPS stimulates platelet secretion and potentiates platelet aggregation through a TLR4/MyD88 and cGMP/PKG-dependent pathway. |
| Databáze: | OpenAIRE |
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