ArticleJournal of molecular and cellular cardiology2012
5-HT(2B) antagonism arrests non-canonical TGF-β1-induced valvular myofibroblast differentiation.
Article in Journal of molecular and cellular cardiology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 97 citations in OpenAlex.
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- Deciphering the Enigma of Calcific Aortic Valve Disease: The Pivotal Role of Animal Models in Unraveling Pathogenesis and Advancing Therapeutic Strategies.Biomedicines · 2025Review
- Strain and hyaluronic acid interact to regulate ovarian cancer cell proliferation, migration, and drug resistance.Mechanobiology in medicine · 2024Article
- Development of a Peripherally Restricted 5-HTJACC. Basic to translational science · 2023Article
- 2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery.Journal of medicinal chemistry · 2023Review
- The Role of Platelets in the Pathogenesis and Pathophysiology of Adenomyosis.Journal of clinical medicine · 2023Review
- Decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation.Science translational medicine · 2023Article
- Unravelling the role of Sildenafil and SB204741 in suppressing fibrotic potential of peritoneal fibroblasts obtained from PD patients.Frontiers in pharmacology · 2023Article
- Inflammatory serum factors from aortic valve stenosis patients modulate sex differences in valvular myofibroblast activation and osteoblast-like differentiation.Biomaterials science · 2022Article
- Models and Techniques to Study Aortic Valve CalcificationFrontiers in pharmacology · 2022Review
- First quantitative dosages: Strong correlations between non-5-HTFrontiers in cardiovascular medicine · 2022Article
- Targeting 5-HTCirculation · 2021Article
- On Valve Interstitial Cell Signaling: The Link Between Multiscale Mechanics and Mechanobiology.Cardiovascular engineering and technology · 2021Review
- Serotonin receptor type 2B activation augments TNF-α-induced matrix mineralization in murine valvular interstitial cells.Journal of cellular biochemistry · 2021Article
- Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Src-family Protein Tyrosine Kinases: A promising target for treating Cardiovascular Diseases.International journal of medical sciences · 2021Review
- Mechanoregulation of Vascular Endothelial Growth Factor Receptor 2 in Angiogenesis.Frontiers in cardiovascular medicine · 2021Review
- Dissecting Calcific Aortic Valve Disease-The Role, Etiology, and Drivers of Valvular Fibrosis.Frontiers in cardiovascular medicine · 2021Review
- International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function.Pharmacological reviews · 2021Review
- Elastogenesis Correlates With Pigment Production in Murine Aortic Valve Leaflets.Frontiers in cardiovascular medicine · 2021Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.