Serotonin mechanisms in heart valve disease I: serotonin-induced up-regulation of transforming growth factor-beta1 via G-protein signal transduction in aortic valve interstitial cells.
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)-beta 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-beta1 expression and activity because of serotonin receptor-mediated signal transduction with activation of Galphaq, 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-beta1 and other proteins associated with TGF-beta expression, including TGF-beta receptors I and II, latent TGF-beta-associated peptide (LAP), and alpha-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-beta1 mRNA production and increased TGF-beta1 activity. 5-HT also increased collagen biosynthesis at the dosages studied. Furthermore, TGF-beta1 added to SAVIC cultures increased the production of sulfated glycan and hyaluronic acid. In addition, overexpression of Galphaq using an adenoviral expression vector for a constitutively active Galphaq mutant (Q209L-Galphaq) resulted in increased phospholipase C activity as well as up-regulation of TGF-beta expression and activity. These results strongly support the view that G-protein-related signal transduction is involved in 5-HT up-regulation of TGF-beta1. In conclusion, 5-HT-associated valve disease may be, in part, because of TGF-beta1 mechanisms.
Jian
Bo
B
Cardiology Research Laboratory, Children's Hospital of Philadelphia, 3416 Civic Center Boulevard, Philadelphia, PA 19104-4318, USA.
Xu
Jie
J
Connolly
Jeanne
J
Savani
Rashmin C
RC
Narula
Navneet
N
Liang
Bruce
B
Levy
Robert J
RJ
D000199:Actins / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001021:Aortic Valve / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006349:Heart Valve Diseases / Q000378:metabolism* / Q000503:physiopathology; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D008297:Male; D015290:Second Messenger Systems / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D012756:Sheep; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D010738:Type C Phospholipases / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D000199:Actins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D012701:Serotonin; D006820:Hyaluronic Acid; D010738:Type C Phospholipases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins