Identification of FDA-approved drugs that induce heart regeneration in mammals

Mahmoud Salama Ahmed; Ngoc Uyen Nhi Nguyen; Yuji Nakada; Ching Cheng Hsu; Ayman Farag; Nicholas T. Lam; Ping Wang; Suwannee Thet; Ivan Menendez-Montes; Waleed M. Elhelaly; Xi Lou; Ilaria Secco; Mateusz Tomczyk; Lorena Zentilin; Jimin Pei; Miao Cui; Matthieu Dos Santos; Xiaoye Liu; Yan Liu; David Zaha; Gregory Walcott; Diana R. Tomchick; Chao Xing; Cheng Cheng Zhang; Nick V. Grishin; Mauro Giacca; Jianyi Zhang; Hesham A. Sadek

doi:10.1038/s44161-024-00450-y

Identification of FDA-approved drugs that induce heart regeneration in mammals

Mahmoud Salama Ahmed, Ngoc Uyen Nhi Nguyen, Yuji Nakada, Ching Cheng Hsu, Ayman Farag, Nicholas T. Lam, Ping Wang, Suwannee Thet, Ivan Menendez-Montes, Waleed M. Elhelaly, Xi Lou, Ilaria Secco, Mateusz Tomczyk, Lorena Zentilin, Jimin Pei, Miao Cui, Matthieu Dos Santos, Xiaoye Liu, Yan Liu, David ZahaGregory Walcott, Diana R. Tomchick, Chao Xing, Cheng Cheng Zhang, Nick V. Grishin, Mauro Giacca, Jianyi Zhang, Hesham A. Sadek

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3 Scopus citations

Abstract

Targeting Meis1 and Hoxb13 transcriptional activity could be a viable therapeutic strategy for heart regeneration. In this study, we performd an in silico screening to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the resolved crystal structure of Meis1 and Hoxb13 bound to DNA. Paromomycin (Paro) and neomycin (Neo) induced proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity by luciferase assay and disruption of DNA binding by electromobility shift assay. X-ray crystal structure revealed that both Paro and Neo bind to Meis1 near the Hoxb13-interacting domain. Administration of Paro–Neo combination in adult mice and in pigs after cardiac ischemia/reperfusion injury induced cardiomyocyte proliferation, improved left ventricular systolic function and decreased scar formation. Collectively, we identified FDA-approved drugs with therapeutic potential for induction of heart regeneration in mammals.

Original language	English (US)
Pages (from-to)	372-388
Number of pages	17
Journal	Nature Cardiovascular Research
Volume	3
Issue number	3
DOIs	https://doi.org/10.1038/s44161-024-00450-y
State	Published - Mar 2024

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology (miscellaneous)
Cell Biology
Medicine (miscellaneous)
Cardiology and Cardiovascular Medicine

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Ahmed, M. S., Nguyen, N. U. N., Nakada, Y., Hsu, C. C., Farag, A., Lam, N. T., Wang, P., Thet, S., Menendez-Montes, I., Elhelaly, W. M., Lou, X., Secco, I., Tomczyk, M., Zentilin, L., Pei, J., Cui, M., Dos Santos, M., Liu, X., Liu, Y., ... Sadek, H. A. (2024). Identification of FDA-approved drugs that induce heart regeneration in mammals. Nature Cardiovascular Research, 3(3), 372-388. https://doi.org/10.1038/s44161-024-00450-y

Ahmed, MS, Nguyen, NUN, Nakada, Y, Hsu, CC, Farag, A, Lam, NT, Wang, P, Thet, S, Menendez-Montes, I, Elhelaly, WM, Lou, X, Secco, I, Tomczyk, M, Zentilin, L, Pei, J, Cui, M, Dos Santos, M, Liu, X, Liu, Y, Zaha, D, Walcott, G, Tomchick, DR , Xing, C , Zhang, CC , Grishin, NV, Giacca, M, Zhang, J & Sadek, HA 2024, 'Identification of FDA-approved drugs that induce heart regeneration in mammals', Nature Cardiovascular Research, vol. 3, no. 3, pp. 372-388. https://doi.org/10.1038/s44161-024-00450-y

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abstract = "Targeting Meis1 and Hoxb13 transcriptional activity could be a viable therapeutic strategy for heart regeneration. In this study, we performd an in silico screening to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the resolved crystal structure of Meis1 and Hoxb13 bound to DNA. Paromomycin (Paro) and neomycin (Neo) induced proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity by luciferase assay and disruption of DNA binding by electromobility shift assay. X-ray crystal structure revealed that both Paro and Neo bind to Meis1 near the Hoxb13-interacting domain. Administration of Paro–Neo combination in adult mice and in pigs after cardiac ischemia/reperfusion injury induced cardiomyocyte proliferation, improved left ventricular systolic function and decreased scar formation. Collectively, we identified FDA-approved drugs with therapeutic potential for induction of heart regeneration in mammals.",

author = "Ahmed, {Mahmoud Salama} and Nguyen, {Ngoc Uyen Nhi} and Yuji Nakada and Hsu, {Ching Cheng} and Ayman Farag and Lam, {Nicholas T.} and Ping Wang and Suwannee Thet and Ivan Menendez-Montes and Elhelaly, {Waleed M.} and Xi Lou and Ilaria Secco and Mateusz Tomczyk and Lorena Zentilin and Jimin Pei and Miao Cui and {Dos Santos}, Matthieu and Xiaoye Liu and Yan Liu and David Zaha and Gregory Walcott and Tomchick, {Diana R.} and Chao Xing and Zhang, {Cheng Cheng} and Grishin, {Nick V.} and Mauro Giacca and Jianyi Zhang and Sadek, {Hesham A.}",

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AU - Farag, Ayman

AU - Lam, Nicholas T.

AU - Wang, Ping

AU - Thet, Suwannee

AU - Menendez-Montes, Ivan

AU - Elhelaly, Waleed M.

AU - Lou, Xi

AU - Secco, Ilaria

AU - Tomczyk, Mateusz

AU - Zentilin, Lorena

AU - Pei, Jimin

AU - Cui, Miao

AU - Dos Santos, Matthieu

AU - Liu, Xiaoye

AU - Liu, Yan

AU - Zaha, David

AU - Walcott, Gregory

AU - Tomchick, Diana R.

AU - Xing, Chao

AU - Zhang, Cheng Cheng

AU - Grishin, Nick V.

AU - Giacca, Mauro

AU - Zhang, Jianyi

AU - Sadek, Hesham A.

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Identification of FDA-approved drugs that induce heart regeneration in mammals

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