A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Chronic Intake of the Selective Serotonin Reuptake Inhibitor Fluoxetine Enhances Atherosclerosis
Tekijät: Martina Rami, Raquel Guillamat-Prats, Petteri Rinne, Melanie Salvermoser, Larisa Ring, Mariaelvy Bianchini, Xavier Blanchet, Remco T.A. Megens, Yvonne Döring, Barbara Walzog, Oliver Soehnlein, Christian Weber, Alexander Faussner, Sabine Steffens
Kustantaja: LIPPINCOTT WILLIAMS & WILKINS
Julkaisuvuosi: 2018
Journal: Arteriosclerosis, Thrombosis, and Vascular Biology
Tietokannassa oleva lehden nimi: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Lehden akronyymi: ARTERIOSCL THROM VAS
Vuosikerta: 38
Numero: 5
Aloitussivu: 1007
Lopetussivu: 1019
Sivujen määrä: 13
ISSN: 1079-5642
eISSN: 1524-4636
DOI: https://doi.org/10.1161/ATVBAHA.117.310536
Objective Cardiovascular diseases and depression are the leading causes of disability in Western countries. Clinical data on potential cardiovascular effects of serotonin reuptake inhibitors (SSRIs), the most commonly used antidepressant drugs, are controversial. In addition to blocking serotonin reuptake transporter in the brain, SSRIs deplete the major peripheral serotonin (5-hydroxytryptamine [5-HT]) storage by inhibiting serotonin reuptake transporter-mediated uptake in platelets. In this study, we aimed to investigate the effect of chronic SSRI intake on the development of atherosclerosis.Approach and Results Treatment of apolipoprotein E-deficient mice with the SSRI fluoxetine for 2, 4, or 16 weeks increased atherosclerotic lesion formation, with most pronounced effect during early plaque development. Intravital microscopy of carotid arteries revealed enhanced myeloid cell adhesion on fluoxetine treatment. Mechanistically, we found that fluoxetine augmented vascular permeability and increased chemokine-induced integrin-binding activity of circulating leukocytes. In vitro stimulation of murine blood demonstrated that fluoxetine, but not 5-HT, could directly promote 1 and 2 integrin activation provided C-C motif chemokine ligand 5 was also present. Similar effects were observed with the SSRI escitalopram. Enhanced C-C motif chemokine ligand 5-induced integrin activation by fluoxetine was also confirmed in a human neutrophil-like cell line. In contrast to the proatherogenic properties of fluoxetine, pharmacological inhibition of the peripheral 5-HT synthesizing enzyme tryptophan hydroxylase 1 did not promote atherosclerosis, suggesting that the proatherogenic effect of fluoxetine occurs independent of peripheral 5-HT depletion.Conclusions SSRI intake may promote atherosclerosis and therefore potentially increase the risk for acute cardiovascular events by a mechanism that is independent of 5-HT depletion.
