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VASCULAR BIOLOGY

Advanced glycation end products elicit externalization of phosphatidylserine in a subpopulation of platelets via 5-HT_2A/2C receptors

¹Faculty of Medical Sciences, Framlington Place, Newcastle University, Newcastle-Upon-Tyne, United Kingdom; and ²Gambro Corporate Research, Hechingen, Germany

Submitted 3 November 2006 ; accepted in final form 30 March 2007

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- inhibitor rottlerin and the serotonin [5-hydroxytryptamine (5-HT)]_2A/2C receptor antagonist ritanserin in a dose-dependent manner. Moreover, the 5-HT_2A/2C receptor agonist 1,2,5-dimethoxy-4-iodophenyl-2-aminopropane mimicked the effect of HSA-AGE on PS externalization. These data demonstrate, for the first time, that HSA-AGE stimulates PS externalization in a subpopulation of platelets via the 5-HT_2A/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.

signal transduction; thrombosis; caspase-3

This article has been cited by other articles:

				Y. Wang, W. Beck, R. Deppisch, S. M. Marshall, N. A. Hoenich, and M. G. Thompson Differential effects of dialysis and ultrafiltrate from individuals with CKD, with or without diabetes, on platelet phosphatidylserine externalization Am J Physiol Renal Physiol, January 1, 2008; 294(1): F220 - F228. [Abstract] [Full Text] [PDF]