Daily variations of platelet aggregation in relation to blood and plasma serotonin in diabetes

Małyszko, Jolanta; Urano, Tetsumei; Knöfler, Ralf; Taminato, A; Takai, Yoshimi; Takada, Yumiko; Takada, Akikazu

doi:10.1016/0049-3848(94)90231-3

Cited by 81 publications

(53 citation statements)

References 23 publications

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“…Citalopram-prepared water was added to a water dispenser, and mice were given full access to either non-treated control or citalopram-treated water. Mice were exposed to citalopram-treated water for 6-days, 1 day beyond the lifetime of a circulating platelet in a mouse (22), to model chronic loss of SERT function in the periphery but minimize central nervous systems effects. After 6 days, mice were euthanized, and experiments were performed as indicated.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, we found that ADP-mediated ␣IIb␤3 activation was reduced in SERT Ϫ/Ϫ and citalopram-treated platelets due to loss of 5-HT 2A R signaling and surface expression. determine whether SSRIs alter blood 5-HT homeostasis, mice were exposed to citalopram-treated water for 6 days, 1 day beyond the lifetime of a circulating platelet in a mouse (22). We used high performance liquid chromatography (HPLC) to measure whole blood levels of 5-HT and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA).…”

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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: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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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“…28) and a lack of understanding of the roles of 5-HT in the peripheral systems. One way by which physiological levels of 5-HT may have an effect on vascular tone is through the interaction with other vasoactive substances including ET-1, which could exacerbate the pathophysiological mechanisms.Evidence suggests that in the diabetic condition, there are elevated levels of 5-HT and ET-1, and they can both enhance each other's actions in vitro (17,19,28), but the physiological effect of this interaction, underlying molecular mechanisms, as well as their role in vascular remodeling in diabetes and vascular contraction are not yet completely elucidated. It is important to understand 5-HT/ET-1 interaction mechanisms that may accelerate the development cardiovascular complications such as hypertension and atherosclerosis, which commonly occur at an increased rate in diabetic patients compared with their age-matched controls.…”

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confidence: 99%

Molecular interactions of serotonin (5-HT) and endothelin-1 in vascular smooth muscle cells: in vitro and ex vivo analyses

Bhaskaran

Zaluski

Banes-Berceli

2014

American Journal of Physiology-Cell Physiology

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Bhaskaran S, Zaluski J, Banes-Berceli A. Molecular interactions of serotonin (5-HT) and endothelin-1 in vascular smooth muscle cells: in vitro and ex vivo analyses. Am J Physiol Cell Physiol 306: C143-C151, 2014. First published November 6, 2013; doi:10.1152/ajpcell.00247.2013.-Elevated levels of serotonin (5-HT) and endothelin-1 (ET-1) may be involved in cardiovascular complications of diabetes mellitus. Data suggest supraphysiological concentrations of 5-HT (10 Ϫ6 M) potentiate the ability of ET-1 to stimulate DNA synthesis and vascular smooth muscle cell (VSMC) proliferation in vitro via activation of mitogen-activated protein kinase (p42/44 MAPK) and Janus kinase 2 (JAK2) pathways. Additionally, 5-HT enhances agonist-induced contractions via p42/44 MAPK and an unknown tyrosine kinase. However, the exact mechanisms of the 5-HT/ET-1 interactions and whether these effects occur at physiological levels (10 Ϫ9 M) are unknown. Therefore, we hypothesized that interactions between 5-HT and ET-1 at physiological concentrations in VSMC enhanced activation of both p42/44 MAPK and JAK2 pathways contributing to vascular growth and contractile responses. With the use of rat VSMC and Western blot analysis, our data suggest no effect of acute (30 min) preincubation with 5-HT (10 Ϫ9 M) and/or ET-1 (10 Ϫ9 M) on the activation of either pathway in normal or high glucose conditions. To determine if there was altered vascular reactivity in intact vessels we tested the effects of 5-HT and ET-1 interaction using myographs to measure isometric contractions of rat thoracic aortic rings. 5-HT (10 Ϫ9 M) and ET-1 (10 Ϫ12 M) stimulate enhanced contractile responses to each other that were inhibited by JAK2 and p42/44 MAPK antagonists. Our findings demonstrate that both 5-HT and ET-1 at physiological concentrations could interact with each other and activate p42/44 MAPK and JAK2 signaling pathways to cause an increase in smooth muscle contraction that could lead to altered vascular function. diabetes; serotonin (5-HT); endothelin-1 (ET-1); vascular smooth muscle cell (VSMC); p42/44 mitogen-activated protein kinase (p42/44 MAPK); Janus kinase 2 (JAK2) DIABETES MELLITUS IS A LEADING cause of renal disease and an independent risk factor for cardiovascular disease complications in the United States. Accumulating evidence suggests that serotonin [5-hydroxytryptamine (5-HT)], a well-known mitogen and a potent vasoconstrictor, may also stimulate pathological processes in diabetes (16). 5-HT has been associated with cardiovascular diseases such as atherosclerosis (10) and pulmonary hypertension (14), but it has been overlooked in some diseases because of its low circulating physiological levels (estimated to be in the 10 Ϫ9 M range; Ref. 28) and a lack of understanding of the roles of 5-HT in the peripheral systems. One way by which physiological levels of 5-HT may have an effect on vascular tone is through the interaction with other vasoactive substances including ET-1, which could exacerbate the pathophysiological mechanisms.Evidence suggests...

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“…Plasma 5-HT concentrations have been reported to be high in diabetic patients (1,2); this may be one of the underlying mechanisms of diabetes complications. The 5-HT 2A receptor has been identified in glomerular mesangial cells (3), suggesting involvement of 5-HT in the development of diabetic nephropathy through proliferation and matrix sysnthesis in mesangial lesions.…”

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confidence: 99%

Association Between Urinary Albumin Excretion and Plasma 5-Hydroxyindole-3-Acetic Acid Concentration in Men With Type 2 Diabetes

et al. 2007

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Serotonin (5-hydroxytryptamine [5-HT]) mediates vasoconstriction and induces the activation of platelets, which may promote atherosclerosis. Plasma 5-HT concentrations have been reported to be high in diabetic patients (1,2); this may be one of the underlying mechanisms of diabetes complications. The 5-HT 2A receptor has been identified in glomerular mesangial cells (3), suggesting involvement of 5-HT in the development of diabetic nephropathy through proliferation and matrix sysnthesis in mesangial lesions. Male sex is an independent risk factor for cardiovascular disease (4). Moreover, elevated urinary albumin excretion (UAE) has been reported to be associated with increased risk of cardiovascular mortality (5). Few studies have examined the association between plasma 5-HT concentration and atherosclerosis (6). To our knowledge, a relationship between plasma 5-HT concentration and degree of UAE has never been explored in men with type 2 diabetes. In this study, we evaluated the relationships between plasma 5-hydroxyindole-3-acetic acid (5-HIAA), a derivative end product of 5-HT, concentration and degree of UAE, and markers of subclinical atherosclerosis, such as pulse wave velocity (PWV), anklebrachial index (ABI), carotid intimamedia thickness (IMT), or plaque score in men with type 2 diabetes.RESEARCH DESIGN AND METHODS -The relationships of plasma 5-HIAA concentrations with degree of UAE and major cardiovascular risk factors were investigated in 205 consecutive men with type 2 diabetes recruited from the outpatient clinic at the Kyoto Prefectural University of Medicine (Kyoto, Japan). Additionally, the relationships between plasma 5-HIAA concentration and PWV or ABI (n ϭ 160) and between plasma 5-HIAA concentration and IMT or plaque score (n ϭ 102) were investigated in a subgroup of patients.Plasma 5-HIAA concentrations (normal range 1.8 -6.1 ng/ml) were measured by high-performance liquid chromatography. The intra-assay coefficients of variation (CVs) were 2.1, 2.0, and 0.9% for plasma 5-HIAA concentrations of 25.27, 41.30, and 95.09 ng/ml, respectively, and the interassay CVs were 3.9, 3.3, and 2.4% for plasma 5-HIAA concentrations of 7.45, 20.55, and 60.83 ng/ml, respectively. UAE was measured with an immunoturbidimetric assay. A mean value for UAE was determined from three urine collections. Patients were excluded if they were taking any medications that might affect plasma 5-HIAA concentrations (e.g., 5-HT receptor blockers). Approval for the study was obtained from the local research ethics committee, and informed consent was obtained from all participants. Brachial-ankle PWV and ABI were measured using a Colin Waveform Analyzer (form PWV/ABI; Colin Medical Technology, Komaki, Japan) (7). B-mode ultrasonographic imaging of the carotid artery was performed as previously described (8). Because plasma 5-HIAA concentration and UAE showed skewed distributions, log transformation of these values was carried out before performing correlation and regression analysis. The relationships between log (plasma 5-HI...

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Daily variations of platelet aggregation in relation to blood and plasma serotonin in diabetes

Cited by 81 publications

References 23 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

Molecular interactions of serotonin (5-HT) and endothelin-1 in vascular smooth muscle cells: in vitro and ex vivo analyses

Association Between Urinary Albumin Excretion and Plasma 5-Hydroxyindole-3-Acetic Acid Concentration in Men With Type 2 Diabetes

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