Abstract 572: Serotonin and Selective Serotonin Reuptake Inhibitors in Platelet Function and RhoA Activation
Platelet hyperactivity leads to thrombotic disease, underlying cardiovascular (CV) pathologies including stroke and myocardial infarction. Clinical data suggest that selective serotonin reuptake inhibitors (SSRIs) have hemostatic effects, signifying a potentially novel mechanism to treat CV disease. SSRIs target the serotonin transporter (SERT), which maintains dense-granule serotonin (5HT) in platelets. Serotonin is also a platelet agonist, acting through 5HT2A receptors, yet the full role of 5HT in platelet physiology is not well understood. We hypothesized that SERT KO mice, mimicking chronic SSRI treatment, would exhibit a bleeding phenotype due to reduced platelet function. Consistent with previous reports, we demonstrated that SERT KO mice have decreased whole blood 5HT. There were comparable concentrations of the 5HT metabolite 5HIAA, suggesting that overall synthesis and metabolism of 5HT is unchanged. We next demonstrate that there is a bleeding phenotype in the SERT KO mice through a significantly increased tail-bleed time and increased thrombin time (TT) in whole blood. Additionally, SERT KO mice have reduced platelet retraction, a platelet function attributed to decreased RhoA activation. To determine if sub-chronic SSRI treatment alters platelet function, we treated both wild type and a hyperactive platelet (KI) mice with citalopram in drinking water for 6 days, one day exceeding the turnover rate of platelet production (15mg/kg/day). Activation of RhoA was examined to determine if reduced serotonylation leads to reduced platelet function. Collectively, these data suggest that genetic or pharmacological inhibition of SERT activity could lead to reduced platelet function. These findings may be due to a decrease in intracellular 5HT, as 5HT is still present for 5HT2A activation as determined by the presence of the metabolite. Future experiments will examine the mechanism of SSRI-mediated platelet activity attenuation, which may include reduced serotonylation of important signaling molecules.
Author Disclosures: K.H. Oliver: None. H.E. Hamm: None. A.M. Carneiro: None.
- © 2014 by American Heart Association, Inc.