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* Department of Pharmacology and
Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, IL 60612; and
Division of Cardiovascular Medicine, The Gill Heart Institute, University of Kentucky, Lexington, KY 40536
Bacterial 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. In this study, we show that LPS stimulates platelet secretion of dense and 
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 TLR (TLR4), CD14, MD2, and MyD88, and the effect of LPS on platelet activation was abolished by an anti-TLR4-blocking Ab 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 NO synthase and the cGMP-dependent protein kinase (PKG). LPS-induced cGMP elevation was inhibited by an anti-TLR4 Ab or by TLR4 deficiency, suggesting that activation of the cGMP/protein kinase G 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work is supported by American Heart Association National Scientist Development Grant 0430095N and American Heart Association Midwest affiliate Grand-in-Aid 0855698G (to Z.L.), Grants HL68819, HL62350, and 080264 from the National Institutes of Health/National Heart Lung and Blood Institute (to X.D.), and in part by the Centers of Biomedical Research Excellence in Obesity and Cardiovascular Disease Grant P20 RR021954-01A1 from the National Institutes of Health/National Center for Research Resources.
2 Address correspondence and reprint requests to Dr. Zhenyu Li, Division of Cardiovascular Medicine, The Gill Heart Institute, 741 South Limestone Street, Biomedical Biological Sciences Research Building, Room B251, University of Kentucky, Lexington, KY 40536-0200. E-mail address: zhenyuli08{at}uky.edu
3 Abbreviations used in this paper: PKG, cGMP-dependent protein kinase; L-NAME, N
-nitro-L-arginine methyl ester; PRP, platelet-rich plasma.
4 The online version of this article contains supplemental material.
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