TY - JOUR
T1 - Serotonin mechanisms in heart valve disease I
T2 - Serotonin-induced up-regulation of transforming growth factor-β1 via G-protein signal transduction in aortic valve interstitial cells
AU - Jian, Bo
AU - Xu, Jie
AU - Connolly, Jeanne
AU - Savani, Rashmin C.
AU - Narula, Navneet
AU - Liang, Bruce
AU - Levy, Robert J.
N1 - Funding Information:
Supported in part by grants from the National Heart, Lung, and Blood Institute ( RO1 HL38118, T32 HL07915 to R. J. L.; RO1 HL62868 and RO1 HL62472 to R. C. S.; and RO1 HL48225 to B. L. ) and the William J. Rashkind Endowment of the Children's Hospital of Philadelphia.
PY - 2002/12/1
Y1 - 2002/12/1
N2 - 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)-β 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-β1 expression and activity because of serotonin receptor-mediated signal transduction with activation of Gαq, 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-β1 and other proteins associated with TGF-β expression, including TGF-β receptors I and II, latent TGF-β-associated peptide (LAP), and α-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-β1 mRNA production and increased TGF-β1 activity. 5-HT also increased collagen biosynthesis at the dosages studied. Furthermore, TGF-β1 added to SAVIC cultures increased the production of sulfated glycan and hyaluronic acid. In addition, overexpression of Gαq using an adenoviral expression vector for a constitutively active Gαq mutant (Q209L-Gαq) resulted in increased phospholipase C activity as well as up-regulation of TGF-β expression and activity. These results strongly support the view that G-protein-related signal transduction is involved in 5-HT up-regulation of TGF-β1. In conclusion, 5-HT-associated valve disease may be, in part, because of TGF-β1 mechanisms.
AB - 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)-β 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-β1 expression and activity because of serotonin receptor-mediated signal transduction with activation of Gαq, 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-β1 and other proteins associated with TGF-β expression, including TGF-β receptors I and II, latent TGF-β-associated peptide (LAP), and α-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-β1 mRNA production and increased TGF-β1 activity. 5-HT also increased collagen biosynthesis at the dosages studied. Furthermore, TGF-β1 added to SAVIC cultures increased the production of sulfated glycan and hyaluronic acid. In addition, overexpression of Gαq using an adenoviral expression vector for a constitutively active Gαq mutant (Q209L-Gαq) resulted in increased phospholipase C activity as well as up-regulation of TGF-β expression and activity. These results strongly support the view that G-protein-related signal transduction is involved in 5-HT up-regulation of TGF-β1. In conclusion, 5-HT-associated valve disease may be, in part, because of TGF-β1 mechanisms.
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UR - http://www.scopus.com/inward/citedby.url?scp=0036898211&partnerID=8YFLogxK
U2 - 10.1016/S0002-9440(10)64489-6
DO - 10.1016/S0002-9440(10)64489-6
M3 - Article
C2 - 12466127
AN - SCOPUS:0036898211
SN - 0002-9440
VL - 161
SP - 2111
EP - 2121
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -