Abstract 15176: Serotonin Antagonist Inhibits Leukocyte-Endothelial Interactions in Vivo and in vitro: Potential Contribution of Pkc-Dependent Pathway
[Background] Serotonin (5-HT) is an important neurotransmitter and signaling molecule in wide variety of organs including vascular systems. Serotonin-induced platelet activation and smooth muscle cell contraction, via 5-HT2A receptors, plays an important role in atherosclerosis and vascular inflammation. Though 5-HT2A- serotonergic antagonist has been utilized in the treatment of vascular disease, its effect on vascular inflammation such as leukocyte-endothelial interactions has not been demonstrated.
[Method and Results] We examined the effect of Sarpogrelate hydrochloride (SRPO), a 5-HT2A receptor antagonist, on leukocyte-endothelial cell interaction in vivo and in vitro. C57BL/6 mice were fed high-fat high-fructose diet (HFFD) containing 20% fat and 30% fructose, with or without SRPO 5mg/kg/day for 4 weeks. Intravital microscopy of the femoral artery revealed significant leukocyte recruitment after HFFD (p<0.001), which was reduced by SRPO (p<0.01). Serum level of MCP-1 was significantly elevated after HFFD which was also blunted by SRPO. To understand molecular mechanisms under this observation, adhesive interactions of THP-1 cells pretreated with or without SRPO were monitored using HUVEC monolayer activated with PMA (10nM). Activation with PMA (10nM) dramatically induced THP-1 cell adhesion to HUVEC, which was inhibited by SRPO pretreatment. We also found that PMA-triggered activation of PKCα in THP-1 cells was also attenuated by SRPO.
[Conclusion] Current observation suggested that selective serotonin antagonist reduced leukocyte-endothelial cell interactions in vitro and in vivo. Potential mechanism seemed to involve PKCα-dependent activation of leukocytes.
- © 2012 by American Heart Association, Inc.