5-HT(2B) antagonism arrests non-canonical TGF-β1-induced valvular myofibroblast differentiation.

Hutcheson JD, Ryzhova LM, Setola V, Merryman WD
J Mol Cell Cardiol. 2012 53 (5): 707-14

PMID: 22940605 · PMCID: PMC3472096 · DOI:10.1016/j.yjmcc.2012.08.012

Transforming growth factor-β1 (TGF-β1) induces myofibroblast activation of quiescent aortic valve interstitial cells (AVICs), a differentiation process implicated in calcific aortic valve disease (CAVD). The ubiquity of TGF-β1 signaling makes it difficult to target in a tissue specific manner; however, the serotonin 2B receptor (5-HT(2B)) is highly localized to cardiopulmonary tissues and agonism of this receptor displays pro-fibrotic effects in a TGF-β1-dependent manner. Therefore, we hypothesized that antagonism of 5-HT(2B) opposes TGF-β1-induced pathologic differentiation of AVICs and may offer a druggable target to prevent CAVD. To test this hypothesis, we assessed the interaction of 5-HT(2B) antagonism with canonical and non-canonical TGF-β1 pathways to inhibit TGF-β1-induced activation of isolated porcine AVICs in vitro. Here we show that AVIC activation and subsequent calcific nodule formation is completely mitigated by 5-HT(2B) antagonism. Interestingly, 5-HT(2B) antagonism does not inhibit canonical TGF-β1 signaling as identified by Smad3 phosphorylation and activation of a partial plasminogen activator inhibitor-1 promoter (PAI-1, a transcriptional target of Smad3), but prevents non-canonical p38 MAPK phosphorylation. It was initially suspected that 5-HT(2B) antagonism prevents Src tyrosine kinase phosphorylation; however, we found that this is not the case and time-lapse microscopy indicates that 5-HT(2B) antagonism prevents non-canonical TGF-β1 signaling by physically arresting Src tyrosine kinase. This study demonstrates the necessity of non-canonical TGF-β1 signaling in leading to pathologic AVIC differentiation. Moreover, we believe that the results of this study suggest 5-HT(2B) antagonism as a novel therapeutic approach for CAVD that merits further investigation.

Copyright © 2012 Elsevier Ltd. All rights reserved.

MeSH Terms (28)

Actins Animals Aortic Diseases Aortic Valve Calcinosis Cell Differentiation Cells, Cultured Gene Expression Indoles Microfilament Proteins Muscle Proteins Myofibroblasts p38 Mitogen-Activated Protein Kinases Phosphorylation Plasminogen Activator Inhibitor 1 Promoter Regions, Genetic Protein Processing, Post-Translational Protein Transport Pyridines Receptor, Serotonin, 5-HT2B Serotonin 5-HT2 Receptor Antagonists Signal Transduction Smad3 Protein src-Family Kinases Sus scrofa Transcriptional Activation Transforming Growth Factor beta1 Urea

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