title: Autocrine serotonin and transforming growth factor beta 1 signaling mediates spontaneous myxomatous mitral valve disease.
abstract: OBJECTIVE
  Although serotonin and serotoninergic drugs are known to cause myxomatous-like valvulopathy, the role of serotonin in spontaneous myxomatous valve disease (MVD) remains unclear. Tryptophan hydroxylase 1 (TPH1) is the limiting enzyme for peripheral serotonin synthesis, and its expression in myxomatous valves could implicate an autocrine serotonin signaling mechanism. Studies in cultured cells demonstrate a close coupling between serotonin and transforming growth factor beta1 (TGFbeta1) signaling. The study aim was to investigate serotonin and TGFbeta1 signaling in spontaneous MVD.
  
  
  METHODS
  In canine normal and myxomatous mitral valves, target signaling proteins including TPH1, serotonin 2B receptor (5HT(2B)R), serotonin transmembrane transporter (SERT), total and phosphorylated extracellular signaling-regulated kinase (ERK) 1/2, latent TGFbeta1 and TGFbeta1 receptors I and II, were studied using immunohistochemistry and immunoblot analysis. In human myxomatous valves, TPH1 was determined using immunofluorescence and immunoblot analysis.
  
  
  RESULTS
  In canine mitral valves, both 5HT(2B)R and TPH1 were increased in myxomatous valves, whereas SERT, a key protein in serotonin metabolism, was decreased in myxomatous valves. Phosphorylated, but not total, ERK 1/2 was increased in myxomatous valves, consistent with an enhanced active serotonin signaling. The expression of TGFbeta1 receptors I and II, and of latent TGFbeta1, was increased in myxomatous valves. Human myxomatous mitral valves expressed TPH1.
  
  
  CONCLUSIONS
  The expression of TPH1 by canine and human myxomatous valves demonstrates a capacity for local serotonin production. Key signaling protein expression patterns support active serotonin and TGFbeta1 signaling in canine myxomatous valves. These findings implicate an autocrine serotonin and TGFbeta1 mechanism in the pathogenesis of spontaneous MVD.
authors.affiliation: Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Sirilak
authors.initials: S
authors.lastname: Disatian
authors.forename: E Christopher
authors.initials: EC
authors.lastname: Orton
mesh_terms: D000368:Aged; D000818:Animals; D019898:Autocrine Communication; D004285:Dogs; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006349:Heart Valve Diseases / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008943:Mitral Valve / Q000378:metabolism*; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014365:Tryptophan Hydroxylase / Q000378:metabolism
chemical_list: D044403:Receptor, Serotonin, 5-HT2B; D018125:Receptors, Transforming Growth Factor beta; D050486:Serotonin Plasma Membrane Transport Proteins; D053773:Transforming Growth Factor beta1; D012701:Serotonin; D014365:Tryptophan Hydroxylase; D048049:Extracellular Signal-Regulated MAP Kinases