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Theranostics 2021; 11(13):6491-6506. doi:10.7150/thno.55821 This issue Cite

Research Paper

Apilimod alters TGFβ signaling pathway and prevents cardiac fibrotic remodeling

Mathieu Cinato1, Laurie Guitou1, Amira Saidi1, Andrei Timotin1, Erwan Sperazza1, Thibaut Duparc1, Sergey N. Zolov2, Sai Srinivas Panapakkam Giridharan2, Lois S. Weisman2, Laurent O. Martinez1, Jerome Roncalli1,3, Oksana Kunduzova1, Helene Tronchere1*, Frederic Boal1✉*

1. INSERM U1297 I2MC, Toulouse, France and Université Paul Sabatier, Toulouse, France.
2. Life Sciences Institute, University of Michigan, Ann Arbor, USA.
3. Department of Cardiology, Toulouse University Hospital, Toulouse, France.
* These authors equally contributed to this work.

✉ Corresponding author: frederic.boalfr; INSERM U1297 I2MC, Toulouse, France and Université Paul Sabatier, Toulouse, France. +33(0)5 31 22 41 17.

Citation:
Cinato M, Guitou L, Saidi A, Timotin A, Sperazza E, Duparc T, Zolov SN, Giridharan SSP, Weisman LS, Martinez LO, Roncalli J, Kunduzova O, Tronchere H, Boal F. Apilimod alters TGFβ signaling pathway and prevents cardiac fibrotic remodeling. Theranostics 2021; 11(13):6491-6506. doi:10.7150/thno.55821. https://www.thno.org/v11p6491.htm
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Abstract

Graphic abstract

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.

Keywords: Heart failure, fibrotic remodeling, PIKfyve, Apilimod, TGFβ.

Citation styles

APA
Cinato, M., Guitou, L., Saidi, A., Timotin, A., Sperazza, E., Duparc, T., Zolov, S.N., Giridharan, S.S.P., Weisman, L.S., Martinez, L.O., Roncalli, J., Kunduzova, O., Tronchere, H., Boal, F. (2021). Apilimod alters TGFβ signaling pathway and prevents cardiac fibrotic remodeling. Theranostics, 11(13), 6491-6506. https://doi.org/10.7150/thno.55821.

ACS
Cinato, M.; Guitou, L.; Saidi, A.; Timotin, A.; Sperazza, E.; Duparc, T.; Zolov, S.N.; Giridharan, S.S.P.; Weisman, L.S.; Martinez, L.O.; Roncalli, J.; Kunduzova, O.; Tronchere, H.; Boal, F. Apilimod alters TGFβ signaling pathway and prevents cardiac fibrotic remodeling. Theranostics 2021, 11 (13), 6491-6506. DOI: 10.7150/thno.55821.

NLM
Cinato M, Guitou L, Saidi A, Timotin A, Sperazza E, Duparc T, Zolov SN, Giridharan SSP, Weisman LS, Martinez LO, Roncalli J, Kunduzova O, Tronchere H, Boal F. Apilimod alters TGFβ signaling pathway and prevents cardiac fibrotic remodeling. Theranostics 2021; 11(13):6491-6506. doi:10.7150/thno.55821. https://www.thno.org/v11p6491.htm

CSE
Cinato M, Guitou L, Saidi A, Timotin A, Sperazza E, Duparc T, Zolov SN, Giridharan SSP, Weisman LS, Martinez LO, Roncalli J, Kunduzova O, Tronchere H, Boal F. 2021. Apilimod alters TGFβ signaling pathway and prevents cardiac fibrotic remodeling. Theranostics. 11(13):6491-6506.

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