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From the Cardiology Research Laboratory* and the Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia; and the Departments of Pediatrics, Pathology, and Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Clinical disorders associated with increased serotonin [5-hydroxytryptamine (5-HT)] levels, such as carcinoid syndrome, and the use of serotonin agonists, such as fenfluoramine have been associated with a valvulopathy characterized by hyperplastic valvular and endocardial lesions with increased extracellular matrix. Furthermore, 5-HT has been demonstrated to up-regulate transforming growth factor (TGF)-ß in mesangial cells via G-protein signal transduction. We investigated the hypothesis that increased exposure of heart valve interstitial cells to 5-HT may result in increased TGF-ß1 expression and activity because of serotonin receptor-mediated signal transduction with activation of G
q, and subsequently up-regulation of phospholipase C. Thus, in the present study we performed a clinical-pathological investigation of retrieved carcinoid and normal valve cusps using immunohistochemical techniques to detect the presence of TGF-ß1 and other proteins associated with TGF-ß expression, including TGF-ß receptors I and II, latent TGF-ß-associated peptide (LAP), and -smooth muscle actin. Carcinoid valve cusps demonstrated the unusual finding of widespread smooth muscle actin involving the interstitial cells in the periphery of carcinoid nodules; these same cells were also positive for LAP. Normal valve cusps were only focally positive for smooth muscle actin and LAP. In sheep aortic valve interstitial cell cultures 5-HT induced TGF-ß1 mRNA production and increased TGF-ß1 activity. 5-HT also increased collagen biosynthesis at the dosages studied. Furthermore, TGF-ß1 added to SAVIC cultures increased the production of sulfated glycan and hyaluronic acid. In addition, overexpression of Gq using an adenoviral expression vector for a constitutively active Gq mutant (Q209L-Gq) resulted in increased phospholipase C activity as well as up-regulation of TGF-ß expression and activity. These results strongly support the view that G-protein-related signal transduction is involved in 5-HT up-regulation of TGF-ß1. In conclusion, 5-HT-associated valve disease may be, in part, because of TGF-ß1 mechanisms.
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