Chronic Intake of the Selective Serotonin Reuptake Inhibitor Fluoxetine Enhances Atherosclerosis
| Autor: | Petteri Rinne, Xavier Blanchet, Christian Weber, Raquel Guillamat-Prats, Yvonne Döring, Melanie Salvermoser, Alexander Faussner, Martina Rami, Sabine Steffens, Remco T. A. Megens, Mariaelvy Bianchini, Barbara Walzog, Larisa Ring, Oliver Soehnlein |
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| Přispěvatelé: | Biomedische Technologie, RS: CARIM - R3.07 - Structure-function analysis of the chemokine interactome for therapeutic targeting and imaging in atherosclerosis, Biochemie |
| Rok vydání: | 2018 |
| Předmět: |
Carotid Artery Diseases
Male 0301 basic medicine Apolipoprotein E Time Factors Mice Knockout ApoE Pharmacology ACTIVATION Myeloid Cells Chemokine CCL5 ta317 Aorta Depression (differential diagnoses) RISK biology Integrin beta1 Serotonin reuptake DEPRESSION INTEGRIN ALPHA-IIB-BETA-3 Plaque Atherosclerotic Carotid Arteries CARDIOVASCULAR-DISEASE Disease Progression PERIPHERAL SEROTONIN Cardiology and Cardiovascular Medicine Selective Serotonin Reuptake Inhibitors Signal Transduction medicine.drug Blood Platelets Serotonin MYELOID CELL RECRUITMENT Serotonin reuptake inhibitor Integrin Aortic Diseases HL-60 Cells APOLIPOPROTEIN-E Drug Administration Schedule antidepressive agents Capillary Permeability 03 medical and health sciences DEFICIENT Fluoxetine Cell Adhesion medicine Animals Humans Integrin Alpha-IIb/Beta-3 business.industry Atherosclerosis Mice Inbred C57BL MICE Disease Models Animal HEK293 Cells 030104 developmental biology CD18 Antigens integrins biology.protein business |
| Zdroj: | Arteriosclerosis Thrombosis and Vascular Biology, 38(5), 1007-1019. LIPPINCOTT WILLIAMS & WILKINS |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvbaha.117.310536 |
| Popis: | 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 β1 and β2 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. |
| Databáze: | OpenAIRE |
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