5HT2-receptors and serotonin release: Their role in human platelet aggregation

Cerrito, E.; Lazzaro, M.P.; Gaudio, E.; Arminio, P.; Aloisi, Gabriella

doi:10.1016/0024-3205(93)90671-o

Cited by 90 publications

(58 citation statements)

References 14 publications

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“…Our findings indicate that chronic loss of SERT function reduces 5-HT 2A R surface expression and signaling in each of two models of altered 5-HT homeostasis. It has previously been established that 5-HT plays a synergistic role with ADP activation during platelet aggregation (12,13,39,40). Here, we demonstrate that 5-HT 2A R stimulation potentiates ADP-dependent signaling to activate ␣IIb␤3 (i.e.…”

Section: -Ht 2a R Surface Expression Reduced With Lost Sert Functionmentioning

confidence: 52%

“…We examined ADP receptor (P2Y 1 12 or P2Y 1 binding between SERT ϩ/ϩ and SERT Ϫ/Ϫ membrane preparations. Additionally, we measured whole blood ADP levels using an ELISA and observed no difference between SERT ϩ/ϩ and SERT Ϫ/Ϫ preparations (Fig.…”

Section: Adp Levels and Adp Receptor Expression Are Retained In Sertmentioning

confidence: 99%

“…Appropriate platelet activation depends on the timely release of these factors (4,5,12). Platelet aggregation is crucial early in thrombus formation (4,5,13).…”

mentioning

confidence: 99%

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Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor

Oliver

Duvernay

Hamm

et al. 2016

Journal of Biological Chemistry

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Reduced platelet aggregation and a mild bleeding phenotype have been observed in patients chronically taking selective serotonin reuptake inhibitors (SSRIs). However, it remains unclear how SSRIs, which inhibit the plasma membrane serotonin transporter (SERT), modulate hemostasis. Here, we examine how sustained inhibition of SERT activity alters serotonergic signaling and influences platelet activation and hemostasis. In the periphery, serotonin (5-HT) 3 is produced by enterochromaffin cells in the gastrointestinal tract, released into the plasma, and quickly taken up by platelets via the plasma membrane serotonin transporter (SERT). Following uptake, 5-HT is stored in dense granules by the actions of the vesicular monoamine transporter 2 (1-4). Chronic inhibition of SERT through selective serotonin reuptake inhibitors (SSRIs) (e.g. citalopram and paroxetine) leads to dramatically reduced platelet 5-HT granule content (5, 6), altering peripheral 5-HT homeostasis and potentially modifying multiple physiological processes including hemostasis (7-10). Clinically, increased bleeding risk has been observed in patients taking SSRIs, and platelet aggregation is disrupted (5, 11). Here, we have characterized a similar effect in two distinct mouse models of lost SERT function, suggesting that sustained loss of SERT function influences hemostasis. Pharmaceutical blockade (citalopram dosing) or genetic ablation (SERTPlatelet dense granules contain 5-HT along with other platelet agonists including adenosine diphosphate (ADP), thromboxane (TXA2), and histamine. Appropriate platelet activation depends on the timely release of these factors (4, 5, 12). Platelet aggregation is crucial early in thrombus formation (4, 5, 13). Aggregation, which is the bridging of platelet-platelet contacts, requires a conformational alteration in the glycoprotein ␣IIb␤3, leading to its activation and fibrinogen binding. 5-HT has been shown to enhance aggregation in a 5-HT 2A receptor (5-HT 2A R)-dependent manner (4, 14 -17). The 5-HT 2A R is the only serotonergic receptor found on platelets and potentiates platelet responses to weak agonists like ADP (18). Subthreshold concentrations of two different platelet agonists can exert a synergistic effect on platelet activation. One example includes dual ADP and 5-HT activation leading to increases in cytosolic [Ca 2ϩ ] (13). However, the role of 5-HT during in vivo hemostasis remains unclear, particularly in the context of chronic SERT inhibition.To elucidate the underlying mechanisms of SSRI effects on platelet aggregation, a better understanding of acute versus chronic inhibition of SERT function during platelet activation is required. Acute and chronic blockage of SERT function results in distinct scenarios regarding the effects on 5-HT homeostasis. Acute inhibition of SERT blocks the amount of

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Section: -Ht 2a R Surface Expression Reduced With Lost Sert Functionmentioning

confidence: 52%

Section: Adp Levels and Adp Receptor Expression Are Retained In Sertmentioning

confidence: 99%

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Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor

Oliver

Duvernay

Hamm

et al. 2016

Journal of Biological Chemistry

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“…Serotonin may contribute to the onset of CAD through central and peripheral mechanisms. In the periphery, serotonin induces platelet aggregation, and in the presence of endothelial damage induces vasoconstriction and hyperplasia of smooth muscle cells of arteries, conditions that can lead to the formation of thrombi (45,46). The effects of serotonin on platelets are mediated by 5-HT 2A receptors (47), and the reuptake of circulating serotonin in platelets is mediated through its specific transporter (5-HTT).…”

Section: Discussionmentioning

confidence: 99%

Coronary artery disease and depression: Possible role of brain-derived neurotrophic factor and serotonin transporter gene polymorphisms

et al. 2009

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Abstract. Cardiovascular disease (CVD) and depression are two of the most common human health problems. Patients with depression have an increased risk of developing cardiovascular disease and mortality after experiencing a cardiac event. Both diseases are complex disorders that are influenced by genetic and environmental factors. Brain-derived neurotrophic factor (BDNF) plays a critical role in regulating both vascular development and response to injury, and promotes survival, differentiation, and maintenance of neurons in the peripheral and nervous system. Evidence suggests that BDNF can enhance serotoninergic transmission. Serotonin modulates different brain functions and is known to regulate sleep, appetite, pain and inflammation. The aims of the present casecontrol study were to investigate the possible role of BDNF Val66Met, 5-HTTLPR and -1438 G/A polymorphisms in the development of coronary artery disease (CAD) in patients with and without depression. Regarding BDNF, our data suggest an involvement of the AA genotype in the pathogenesis of CAD in females and in the predisposition to CAD associated with depression. Furthermore, it could be argued that the GG genotype is protective against CAD in the female population and against CAD associated with depression. In our CAD population we also observed a significant increase in the L/L genotype and a decrease in the S/L genotype with respect to the controls. A higher frequency of the L allele, responsible for enhancing the efficiency of transcription, was found in CAD patients. These findings may be responsible for the increased capacity of platelet serotonin uptake previously observed in patients with CAD. Although no differences were found for genotype and allelic frequencies of the -1438 G/A polymorphism between the CAD patients and controls, we cannot exclude the possible role of this receptor in coronary artery disease.

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“…Upon platelet activation (especially with high shear) high concentrations of serotonin in the platelets are released from the dense granules [23], and act upon platelet serotonin 5HT 2A receptors to activate more platelets, thus constituting a positive feedback mechanism leading to thrombus growth [24]. The serotonin theory [25] supposes that this serotonin mediation is essential for thrombotic occlusion of diseased coronary arteries, owing to the fact that such occlusions are abolished by antagonism of the platelet 5HT 2A receptor [26,27], even when the major stimulus of adrenaline is applied [28] and also in the circumstances where thrombolysis has failed to clear a complete thrombotic occlusion [29].…”

Section: The Importance Of Platelet Serotonin Positive Feedbackmentioning

confidence: 99%

Commentary: On the Pathophysiology of Coronary Heart Disease

Noble¹

2017

J Med Surg Pathol

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This article highlights some important aspects of the pathophysiology of coronary artery disease, namely:• The distribution of lesions within the arterial tree at sites of low wall shear stress.• The potential role of low flow-mediated arterial dilatation at sites of low wall stress.• Low flow-mediated dilatation leads to low nitric oxide production by the arterial endothelium and consequent reduced protection against lesion formation.• Flow-mediated dilatation is reduced by high lumenal glucose concentration.• The role of the glycocalyx dysfunction in mediating flow-mediated dilatation and consequent reduced NO production by the arterial endothelium and cell adhesion.• Stenoses cause convective acceleration of blood velocity and a consequent increase in platelet shear stress.• Increased platelet shear stress activates platelets with release of serotonin.• Serotonin activates more platelet activation via the 5HT 2A platelet receptor causing a positive feedback and thrombus growth.• Arterial thrombus growth is abolished by 5HT 2A receptor antagonists, the key to improved treatment of the disease.• One 5HT 2A receptor antagonist has been shown in humans to be safe and to cause no excess bleeding from wounds.

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5HT2-receptors and serotonin release: Their role in human platelet aggregation

Cited by 90 publications

References 14 publications

Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor

Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor

Coronary artery disease and depression: Possible role of brain-derived neurotrophic factor and serotonin transporter gene polymorphisms

Commentary: On the Pathophysiology of Coronary Heart Disease

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