Cited by 294Immunotoxicology and immune responsesTGF-β signaling in diseasesCardiac Valve Diseases and Treatments

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Induction of Heart Valve Lesions by Small-Molecule ALK5 Inhibitors

Anderton, Mark J., Mellor, Howard R., Bell, Alex, Sadler, Claire, Pass, Martin, Powell, Steve, Steele, Samantha J., Roberts, Ruth. R. A., Heier, Annabelle·2011·Toxicologic Pathology

DOI 10.1177/0192623311416259

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Abstract

Aberrant signaling by transforming growth factor-β (TGF-β) and its type I (ALK5) receptor has been implicated in a number of human diseases and this pathway is considered a potential target for therapeutic intervention. Transforming growth factor-β signaling via ALK5 plays a critical role during heart development, but the role of ALK5 in the adult heart is poorly understood. In the current study, the preclinical toxicology of ALK5 inhibitors from two different chemistry scaffolds was explored. Ten-week-old female Han Wistar rats received test compounds by the oral route for three to seven days. Both compounds induced histopathologic heart valve lesions characterized by hemorrhage, inflammation, degeneration, and proliferation of valvular interstitial cells. The pathology was observed in all animals, at all doses tested, and occurred in all four heart valves. Immunohistochemical analysis of ALK5 in rat hearts revealed expression in the valves, but not in the myocardium. Compared to control animals, protein levels of ALK5 were unchanged in the heart valves of treated animals. We also observed a physeal dysplasia in the femoro-tibial joint of rats treated with ALK5 inhibitors, a finding consistent with a pharmacological effect described previously with ALK5 inhibitors. Overall, these findings suggest that TGF-β signaling via ALK5 plays a critical role in maintaining heart valve integrity.

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Additional file 4 of Lysine acetyltransferase 14 mediates TGF-β-induced fibrosis in ovarian endometrioma via co-operation with serum response factor
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Authors: Anderton, M. J., Mellor, H. R., Bell, A., Sadler, C., Pass, M., Powell, S., Steele, S. J., Roberts, R. R. A., & Heier, A.
Affiliations: AstraZeneca (United Kingdom) (GB)
Corresponding author: Heier, Annabelle
ORCID: Roberts, Ruth. R. A.
Heier, Annabelle
Venue: Toxicologic Pathology
Publisher: SAGE Publications
Published: 2011-08-22
Volume: 39
Issue: 6
Pages: 916-924
ISSN: 0192-6233 (ISSN-L)
1533-1601
DOI: 10.1177/0192623311416259
OpenAlex: W2140740750
Cited by: 284
References: 55
Citations by year: 2026: 17 · 2025: 18 · 2024: 33 · 2023: 20 · 2022: 27 · 2021: 33 · 2020: 30 · 2019: 20 · 2018: 16 · 2017: 13 · 2016: 17 · 2015: 12 · 2014: 12 · 2013: 8 · 2012: 8
FWCI: 4.12
Type: journal article
Language: en
Open access: closed
Licence: journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations: Toxicologic Pathology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
Keywords: ALK5 inhibitor, heart valve lesions, TGF-beta signaling, valvular interstitial cells, cardiotoxicity, preclinical toxicology, femorotibial joint, small molecule inhibitors
MeSH terms: Receptor, Transforming Growth Factor-beta Type I, Administration, Oral, Animals, Drug Evaluation, Preclinical, Female, Heart Valves, Immunohistochemistry, Signal Transduction, Transforming Growth Factor beta, Rats, Wistar, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Protein Kinase Inhibitors, Rats

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Induction of Heart Valve Lesions by Small-Molecule ALK5 Inhibitors

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