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 TALE 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 of Meis1 and Hoxb13 transcriptional activity could be a viable path toward 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 a number of top 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, two antibiotics induced the proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity. X-ray crystallography demonstrated that both antibiotics bind Meis1 at the Hoxb13 interaction domain. Intriguingly, the combination treatment of these antibiotics induced cardiomyocyte mitosis in vivo in adult mice, and improved left ventricular (LV) systolic function following experimental ischemia/reperfusion injury. Finally, intravenous administration of the antibiotics in pigs following ischemia/reperfusion injury induced cardiomyocyte proliferation, improved LV systolic function, and decreased scar formation. Collectively, these results identify the paromomycin-neomycin combination as FDA-approved drug with therapeutic potential for the induction of heart regeneration in humans.
Regenerating the Cardiovascular System (University of Oxford, UK) (2023) Proc Physiol Soc 52, C14
Poster Communications: Identification of FDA-Approved Drugs that Induce Heart Regeneration in Mammals
Ngoc Uyen Nhi Nguyen1, Mahmoud Salama Ahmed1, Yuji Nakada1, Ching-Cheng Hsu1, Ayman Farag1, Nicholas Lam1, Ping Wang1, Suwannee Thet1, Ivan Menendez-Montes1, Xi Lou1, Ilaria Secco1, Mateusz Tomczyk1, Lorena Zentilin1, Jimin Pei1, Miao Cui1, Gregory Walcott1, Diana Tomchick1, Nick Grishin1, Chao Xing1, Mauro Giacca1, Jianyi Zhang1, Hesham Sadek1,
1The University of Texas Southwestern Medical Center Dallas United States, 2University of Alabama at Birmingham Birmingham United States, 3King's College London London United Kingdom,
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Where applicable, experiments conform with Society ethical requirements.