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| Status |
Public on Jan 18, 2024 |
| Title |
Identification of FDA-Approved Drugs that Induce Heart Regeneration in Mammals [ChIP] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
The inability of the adult human heart to regenerate lost or damaged myocardial tissue has created one of the most pressing public health dilemmas due to the devastating impact of heart failure. Our group and others have outlined several regulators of cardiomyocyte mitosis that may impact the regenerative capacity of the adult myocardium in mammals. Recently, we reported that the transcription factors Meis1 and Hoxb13 regulate postnatal cardiomyocyte cell cycle arrest, where concomitant deletion of both genes induced cardiomyocyte proliferation and myocardial regeneration following ischemic injury. These studies suggest that pharmacological targeting Meis1 and Hoxb13 transcriptional activity could be a viable path towards heart regeneration. Therefore, we performed an in-silico screen to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the published crystal structure of Meis1 and Hoxb13 bound to DNA. Our screen yielded several candidates based on binding profiles to either Meis1 DNA binding domain, Hoxb13 DNA binding domain, or the interface between Meis1 and Hoxb13, as well as safety and side effect profiles. Out of the shortlist of top hits, paromomycin and neomycin 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 EMSA. X-ray crystal structure revealed that both paromomycin and neomycin bind to Meis1 near the Hoxb13 interaction site where they interact with 3 out of the 5 Meis1 amino acids that participate in DNA-binding. The crystal structure also demonstrates that both drugs bind at the interface of Meis1 homodimer, therefore placing one of the Meis1 monomers in a position incompatible with DNA-binding. Importantly, administration of paromomycin-neomycin combination by intraperitoneal injection in mice induced cardiomyocyte proliferation, improved left ventricular (LV) systolic function and decreased scar formation in two models of ischemic reperfusion injury in mice. Finally, dual intravenous administration of the paromomycin-neomycin combination in Yorkshire pigs following cardiac ischemia/reperfusion injury induced cardiomyocyte proliferation, improved LV systolic function, and decreased scar formation. Collectively, we identified paromomycin and neomycin as FDA-approved drugs with therapeutic potential for induction of heart regeneration in humans.
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| Overall design |
Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for Meis1 or Hoxb13 in postnatal day (p) 15 murine hearts that underwent 7 days of combination Paromomycin and Neomycin injection from p7.
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| Contributor(s) |
Sadek HA, Nguyen N, Ahmed MS, Xing C, Liu Y |
| Citation |
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 and Hesham A Sadek. Identification of FDA-approved drugs that induce heart regeneration in mammals. Nat Cardiovasc Res 3, 372-388 (2024). doi:10.1038/s44161-024-00450-y
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| Submission date |
Aug 09, 2023 |
| Last update date |
Apr 19, 2024 |
| Contact name |
Hesham A. Sadek |
| E-mail(s) |
Hesham.sadek@UTSouthwestern.edu
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| Organization name |
UT Southwestern Medical Center
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| Street address |
6000 Harry Hines Blvd
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| City |
Dallas |
| State/province |
TX |
| ZIP/Postal code |
75390 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (16)
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| This SubSeries is part of SuperSeries: |
| GSE240520 |
Identification of FDA-Approved Drugs that Induce Heart Regeneration in Mammals |
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| Relations |
| BioProject |
PRJNA1003797 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE240437_RAW.tar |
5.8 Gb |
(http)(custom) |
TAR (of BIGWIG, BROADPEAK) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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