title: Down-regulation of the serotonin transporter in hyperreactive platelets counteracts the pro-thrombotic effect of serotonin.
abstract: An elevated plasma concentration of serotonin ([5-HT]) is a common feature of cardiovascular disease often associated with enhanced platelet activation and thrombosis. Whether elevated in vivo plasma 5-HT per se represents an independent risk factor for platelet hyperreactivity or only is an epiphenomenon of cardiovascular disease is poorly understood. We examined in vitro and in vivo platelet function following a 24h elevation of plasma [5-HT] in mice. In vivo administration of 5-HT using osmotic minipumps increased plasma [5-HT] in treated mice compared to control mice instrumented with saline loaded pumps. 5-HT infusion did not increase systolic blood pressure, but markers of platelet activation including P-selectin and (PE)Jon/A staining were increased and these findings coincided with the enhanced aggregation of isolated platelets in response to type I fibrillar collagen. Tail bleeding times and the time to occlusion following chemical damage to the carotid artery were shortened in 5-HT-infused mice. 5-HT-infused mice were treated with paroxetine (Prx) to block 5-HT uptake via the serotonin transporter (SERT). Prx lowered platelet [5-HT] and attenuated platelet activation and aggregation. These results and our biochemical indices of enhanced 5-HT intracellular signaling in the platelets of 5-HT-infused mice reveal a mechanistic link between elevated plasma [5-HT], abnormal intracellular 5-HT signaling and accentuated platelet aggregation. Although a down-regulation of the serotonin transporter (SERT) on the platelet surface may counteract the pro-thrombotic influence of elevated plasma [5HT], this compensatory mechanism may fail to prevent the increased thrombotic risk caused by elevated plasma [5-HT].
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, The University of Arkansas for Medical Sciences, Arkansas, USA.
authors.forename: Endrit
authors.initials: E
authors.lastname: Ziu
authors.forename: Charles P
authors.initials: CP
authors.lastname: Mercado
authors.forename: Yicong
authors.initials: Y
authors.lastname: Li
authors.forename: Preeti
authors.initials: P
authors.lastname: Singh
authors.forename: Billow A
authors.initials: BA
authors.lastname: Ahmed
authors.forename: Samuel
authors.initials: S
authors.lastname: Freyaldenhoven
authors.forename: Shelly
authors.initials: S
authors.lastname: Lensing
authors.forename: Jerry
authors.initials: J
authors.lastname: Ware
authors.forename: Fusun
authors.initials: F
authors.lastname: Kilic
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015539:Platelet Activation; D010974:Platelet Aggregation; D010976:Platelet Count; D012701:Serotonin / Q000097:blood / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D013927:Thrombosis / Q000097:blood*; D011503:Transglutaminases / Q000378:metabolism; D020695:rab4 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin; D011503:Transglutaminases; D020695:rab4 GTP-Binding Proteins; D002118:Calcium