Apilimod alters TGFβ signaling pathway and prevents cardiac fibrotic remodeling
Autor: | Mathieu, Cinato, Laurie, Guitou, Amira, Saidi, Andrei, Timotin, Erwan, Sperazza, Thibaut, Duparc, Sergey N, Zolov, Sai Srinivas Panapakkam, Giridharan, Lois S, Weisman, Laurent O, Martinez, Jerome, Roncalli, Oksana, Kunduzova, Helene, Tronchere, Frederic, Boal |
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Rok vydání: | 2020 |
Předmět: |
Male
Morpholines Drug Evaluation Preclinical Heart failure Mice Phosphatidylinositol 3-Kinases Ventricular Dysfunction Left Apilimod Transforming Growth Factor beta Animals Humans Single-Blind Method Cells Cultured Ventricular Remodeling Myocardium Hydrazones Receptor Transforming Growth Factor-beta Type II TGFβ Fibroblasts PIKfyve Fibrosis Rats Mice Inbred C57BL HEK293 Cells Pyrimidines fibrotic remodeling HeLa Cells Signal Transduction Research Paper |
Zdroj: | Theranostics |
ISSN: | 1838-7640 |
Popis: | Rationale: TGFβ signaling pathway controls tissue fibrotic remodeling, a hallmark in many diseases leading to organ injury and failure. In this study, we address the role of Apilimod, a pharmacological inhibitor of the lipid kinase PIKfyve, in the regulation of cardiac pathological fibrotic remodeling and TGFβ signaling pathway. Methods: The effects of Apilimod treatment on myocardial fibrosis, hypertrophy and cardiac function were assessed in vivo in a mouse model of pressure overload-induced heart failure. Primary cardiac fibroblasts and HeLa cells treated with Apilimod as well as genetic mutation of PIKfyve in mouse embryonic fibroblasts were used as cell models. Results: When administered in vivo, Apilimod reduced myocardial interstitial fibrosis development and prevented left ventricular dysfunction. In vitro, Apilimod controlled TGFβ-dependent activation of primary murine cardiac fibroblasts. Mechanistically, both Apilimod and genetic mutation of PIKfyve induced TGFβ receptor blockade in intracellular vesicles, negatively modulating its downstream signaling pathway and ultimately dampening TGFβ response. Conclusions: Altogether, our findings propose a novel function for PIKfyve in the control of myocardial fibrotic remodeling and the TGFβ signaling pathway, therefore opening the way to new therapeutic perspectives to prevent adverse fibrotic remodeling using Apilimod treatment. |
Databáze: | OpenAIRE |
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