Abstract 11220: Serotonin is Necessary for GPIIbIIIa Activation and Alpha Granule Exocytosis
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. The serotonin transporter (SERT) is the main target of SSRIs, 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 examined physiological markers of platelet activity. The SERT KO mice had a significantly increased tail-bleed time as compared to controls. Increased thrombin time (TT) in whole blood was also observed. To characterize activation potential for the SERT KO mouse platelets, we used flow cytometry for two platelet markers; JON/A (active GPIIbIIIa) and P-selectin (GP released with alpha-granule exocytosis). We found that both P-selectin and JON/A were significantly reduced in SERT KO platelets in diluted whole blood stimulated with PAR4 activating peptide (PAR4-AP). Decreased expression of active GPIIbIIIa and secretion P-selectin was also observed in gel-filtered human platelets stimulated with PAR4-AP that had been acutely treated with increasing concentrations of the SSRI, citalopram. Collectively, these data suggest that genetic or pharmacological inhibition of SERT activity reduces platelet function. These findings may be due to a decrease in intracellular 5HT. Future experiments will examine the mechanism of SSRI-mediated platelet activity attenuation, which may include reduced serotonylation of important signaling molecules.
- © 2013 by American Heart Association, Inc.