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Advanced glycation end products elicit externalization of phosphatidylserine in a subpopulation of platelets via 5-HT2A/2C receptors

Lookup NU author(s): Emerita Professor Sally Marshall, Dr Nicholas Hoenich, Dr Michael Thompson


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Advanced glycation end products (AGE) are substantially elevated in individuals with diabetes and/or chronic kidney disease (CKD). These patients are at greatly increased risk of cardiovascular events. The purpose of this study was to investigate the novel hypothesis that AGE elicit externalization of the platelet membrane phospholipid phosphatidylserine (PS). This contributes to hemostasis through propagation of the coagulation cascade leading to thrombus formation. Platelet-rich plasma (PRP) was prepared by differential centrifugation, and PS externalization was quantified by a fluorescence- activated cell sorter using annexin V-FITC. Human serum albumin (HSA)-AGE was generated by incubating HSA with glucose for 2, 4, or 6 wk, and total HSA-AGE was assessed by fluorescence intensity. The 2-wk HSA-AGE preparation (0-2 mg/ml) stimulated a concentration-dependent increase in PS externalization in a subpopulation of platelets that was threefold at 2 mg/ml. In contrast, the 4- and 6-wk preparations were maximal at 0.5 mg/ml and fivefold in magnitude. These effects mirrored the change in total HSA-AGE content of the preparations. The PS response was maximal at 10 min and inhibited by the PKC-δ inhibitor rottlerin and the serotonin [5-hydroxytryptamine (5-HT)]2A/2C receptor antagonist ritanserin in a dose-dependent manner. Moreover, the 5-HT2A/2C receptor agonist 1,2,5-dimethoxy-4-iodophenyl-2- aminopropane mimicked the effect of HSAAGE on PS externalization. These data demonstrate, for the first time, that HSA-AGE stimulates PS externalization in a subpopulation of platelets via the 5-HT2A/2C receptor. This may have important consequences for platelet involvement in inflammatory responses and the increased cardiovascular risk observed in individuals with diabetes and/or CKD. Copyright © 2007 the American Physiological Society.

Publication metadata

Author(s): Wang Y, Beck W, Deppisch R, Marshall SM, Hoenich NA, Thompson MG

Publication type: Article

Publication status: Published

Journal: American Journal of Physiology - Cell Physiology

Year: 2007

Volume: 293

Issue: 1

Pages: C328-C336

Print publication date: 01/07/2007

ISSN (print): 0363-6143

ISSN (electronic): 1522-1563

Publisher: American Physiological Society


DOI: 10.1152/ajpcell.00560.2006

PubMed id: 17625040


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