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(American Journal of Pathology. 2002;161:2209-2218.)
© 2002 American Society for Investigative Pathology

Regular Articles

Serotonin Mechanisms in Heart Valve Disease II

The 5-HT₂ Receptor and Its Signaling Pathway in Aortic Valve Interstitial Cells

Jie Xu^*, Bo Jian^*, Richard Chu, Zhibin Lu^*, Quanyi Li^*, John Dunlop, Sharon Rosenzweig-Lipson, Paul McGonigle, Robert J. Levy^* and Bruce Liang

From the Cardiology Research Laboratory,^* Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; the Departments of Medicine and Pharmacology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania; and Wyeth-Ayerst Research, Princeton, New Jersey

Serotonin [5-hydroxytryptamine (5-HT)]-mediated cardiac valvular disease has been commonly observed in patients with carcinoid tumors. Previous research by others using reverse transcriptase-polymerase chain reaction demonstrated that aortic valve cells expressed predominantly 5-HT_2A/2B receptors (5-HT_2AR). Related investigations by our group using sheep aortic valve interstitial cell (SAVIC) cultures demonstrated that 5-HT both up-regulates transforming growth factor (TGF)-ß1 expression and activity, and also results in increased phospholipase C (PLC) activity. Thus, the present study investigated the hypothesis that the 5-HT signaling pathway in SAVICs involves 5-HT₂Rs with associated G-protein signal transduction. The objectives were to functionally characterize in SAVIC cultures the native serotonin receptor subtypes using specific agonists and antagonists, and to delineate the serotonin-signaling pathway. 5-HT administration caused a marked stimulation of PLC activity. SAVIC studies of specific agents that target the 5-HT₂R subtypes indicate that this response seemed to be mediated predominantly by 5-HT_2ARs. Furthermore, the sheep 5-HT_2AR was identified by reverse transcriptase-polymerase chain reaction with sequence confirmation including comparisons to pig and human 5-HT_2AR. Extracellular signal-regulated kinase (Erk 1/2) is a signaling molecule downstream from the 5-HT_2AR. Both a protein kinase C inhibitor, GF109203X, and a Src inhibitor, PP1, attenuated 5-HT-stimulated Erk 1/2 activation. However, a 5-HT_2AR antagonist, MDL 100907, inhibited 5-HT up-regulation of PLC and TGF-ß1, while having far less pronounced effects on Erk 1/2. In conclusion, these studies of the signal transduction activity of SAVICs in response to 5-HT have demonstrated that the 5-HT_2ARs are the most functionally active of the 5-HT₂Rs in this cell type. Furthermore, 5-HT_2ARs are also involved in 5-HT up-regulation of active TGF-ß. 5-HT also mediated strong Erk 1/2 signaling via the MAP-kinase pathway, which was only in part because of 5-HT_2AR activity. Thus, major 5-HT Erk 1/2 signaling beyond that controlled by 5-HT₂Rs must involve other serotonin receptor types and/or secondary signaling events.

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