TY - JOUR
T1 - Chronic Intake of the Selective Serotonin Reuptake Inhibitor Fluoxetine Enhances Atherosclerosis
AU - Rami, Martina
AU - Guillamat-Prats, Raquel
AU - Rinne, Petteri
AU - Salvermoser, Melanie
AU - Ring, Larisa
AU - Bianchini, Mariaelvy
AU - Blanchet, Xavier
AU - Megens, Remco T. A.
AU - Doring, Yvonne
AU - Walzog, Barbara
AU - Soehnlein, Oliver
AU - Weber, Christian
AU - Faussner, Alexander
AU - Steffens, Sabine
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
AB - 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.
KW - antidepressive agents
KW - atherosclerosis
KW - fluoxetine
KW - integrins
KW - serotonin
KW - MYELOID CELL RECRUITMENT
KW - INTEGRIN ALPHA-IIB-BETA-3
KW - CARDIOVASCULAR-DISEASE
KW - PERIPHERAL SEROTONIN
KW - APOLIPOPROTEIN-E
KW - DEPRESSION
KW - MICE
KW - RISK
KW - ACTIVATION
KW - DEFICIENT
U2 - 10.1161/ATVBAHA.117.310536
DO - 10.1161/ATVBAHA.117.310536
M3 - Article
C2 - 29567680
SN - 1079-5642
VL - 38
SP - 1007
EP - 1019
JO - Arteriosclerosis Thrombosis and Vascular Biology
JF - Arteriosclerosis Thrombosis and Vascular Biology
IS - 5
ER -