Abstract 1551: Serotonin Transporter Blockade with Dexfenfluoramine or Fluoxetine increases Serotonin-mediated ERK1/2 Phosphorylation in Heart Valve Interstitial Cells: Implications for Serotonin-related Heart Valve Disease
Dexfenfluoramine (DEX), a serotonin transporter (SERT) inhibitor, when used as an appetite suppressant, either alone or with fenteramine, has been associated with acquired cardiac valve disease attributed to serotonin (5-HT) mechanisms. Previous research from our laboratory has demonstrated that 5-HT G-protein coupled receptors are present in heart valve interstitial cells (HVIC), and that 5-HT stimulation of these receptors results in signal transduction related events including ERK1/2 phosphorylation (ERK1/2p) with upregulation of TGF-Beta1 and associated increased extracellular matrix production. In the present studies we examined the hypothesis that DEX or Fluoxetine (FLU) when administered to HVIC together with 5-HT would result in increased ERK1/2p (per Western blots with densitometry) due to the inability of HVIC to deactivate 5-HT, thus leading to increased and sustained G-protein signaling. Human mitral valves, myxomatous and anatomically normal (autopsy and transplant cases), and canine mitral valves (myxomatous and normal) were obtained. 5-HT type 2B receptors and SERT were demonstrated by immunostaining in all human (n=18) and canine valves (n=10). HVIC canine cultures demonstrated ERK1/2p with 5-HT administration (10−5M) at 5 minutes (p=0.002). DEX or FLU alone (10−5M) resulted in no significant increase in ERK1/2p over baseline. However, DEX at 10−9M plus 5-HT caused a significant increase in ERK1/2p versus 5-HT alone (paired t-test; p=0.016) at 5minutes; FLU caused a similar but delayed increase at 10 minutes. An identical cell culture protocol was carried out using human mitral HVIC which demonstrated results comparable to the canine data, with SERT inhibitors resulting in an increase in 5-HT induced ERK1/2p, but only in the presence of 5-HT. It is concluded that SERT blockade may lead to heart valve disease as a result of increased 5-HT signal transduction due to the continued presence of 5-HT, with subsequent upregulation of TGF-Beta1 and associated events. These findings have important implications concerning the pathogenesis of 5-HT mechanisms in heart valve disease.