Chronic Intake of the Selective Serotonin Reuptake Inhibitor Fluoxetine Enhances Atherosclerosis

Arterioscler Thromb Vasc Biol. 2018 May;38(5):1007-1019. doi: 10.1161/ATVBAHA.117.310536. Epub 2018 Mar 22.

Abstract

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.

Keywords: antidepressive agents; atherosclerosis; fluoxetine; integrins; serotonin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / drug effects*
  • Aorta / metabolism
  • Aorta / pathology
  • Aortic Diseases / blood
  • Aortic Diseases / chemically induced*
  • Aortic Diseases / genetics
  • Aortic Diseases / pathology
  • Atherosclerosis / blood
  • Atherosclerosis / chemically induced*
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism
  • CD18 Antigens / blood
  • Capillary Permeability / drug effects
  • Carotid Arteries / drug effects*
  • Carotid Arteries / metabolism
  • Carotid Arteries / pathology
  • Carotid Artery Diseases / blood
  • Carotid Artery Diseases / chemically induced*
  • Carotid Artery Diseases / genetics
  • Carotid Artery Diseases / pathology
  • Cell Adhesion / drug effects
  • Chemokine CCL5 / blood
  • Disease Models, Animal
  • Disease Progression
  • Drug Administration Schedule
  • Fluoxetine / administration & dosage
  • Fluoxetine / toxicity*
  • HEK293 Cells
  • HL-60 Cells
  • Humans
  • Integrin beta1 / blood
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE
  • Myeloid Cells / drug effects
  • Myeloid Cells / metabolism
  • Plaque, Atherosclerotic*
  • Selective Serotonin Reuptake Inhibitors / administration & dosage
  • Selective Serotonin Reuptake Inhibitors / toxicity*
  • Serotonin / blood
  • Signal Transduction
  • Time Factors

Substances

  • CD18 Antigens
  • Ccl5 protein, mouse
  • Chemokine CCL5
  • Integrin beta1
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Serotonin