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Induction of Heart Valve Lesions by Small-Molecule ALK5 Inhibitors
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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“Initial dose escalation studies of galunisertib or other TβRI kinase inhibitors mandated monitoring for cardiotoxicity due to heart valve dysplasia that was observed in rats and dogs receiving high doses of drug340,341.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [341]
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Metadata
- 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
- Venue
- Toxicologic Pathology
- Publisher
- SAGE Publications
- Published
- 2011-08-22
- Volume
- 39
- Issue
- 6
- Pages
- 916-924
- ISSN
- 0192-6233 (ISSN-L)
- 1533-1601
- 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
- 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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