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

Autor: Ahmed MS; Division of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.; These authors contributed equally: Mahmoud Salama Ahmed, Ngoc Uyen Nhi Nguyen., Nguyen NUN; Division of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.; These authors contributed equally: Mahmoud Salama Ahmed, Ngoc Uyen Nhi Nguyen., Nakada Y; Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham, Birmingham, AL, USA., Hsu CC; Division of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Farag A; Division of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Lam NT; Division of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Wang P; Division of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Thet S; Division of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Menendez-Montes I; Division of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Elhelaly WM; Division of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Lou X; Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham, Birmingham, AL, USA., Secco I; School of Cardiovascular and Metabolic Medicine & Sciences and British Heart Foundation Centre of Research Excellence, King's College London, London, UK., Tomczyk M; School of Cardiovascular and Metabolic Medicine & Sciences and British Heart Foundation Centre of Research Excellence, King's College London, London, UK., Zentilin L; Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy., Pei J; Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Cui M; Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.; Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.; Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Dos Santos M; Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.; Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.; Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Liu X; Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Liu Y; Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Zaha D; Division of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Walcott G; Division of Cardiovascular Diseases, Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA., Tomchick DR; Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Xing C; Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Zhang CC; Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Grishin NV; Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Giacca M; School of Cardiovascular and Metabolic Medicine & Sciences and British Heart Foundation Centre of Research Excellence, King's College London, London, UK.; Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.; Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy., Zhang J; Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham, Birmingham, AL, USA., Sadek HA; Division of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.; Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.; Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Jazyk: angličtina
Zdroj: Nature cardiovascular research [Nat Cardiovasc Res] 2024 Mar; Vol. 3 (3), pp. 372-388. Date of Electronic Publication: 2024 Mar 11.
DOI: 10.1038/s44161-024-00450-y
Abstrakt: 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.
Competing Interests: Competing interests M.G. is founder, consultant, member of the board and equity holder in Forcefield Therapeutics, Heqet Therapeutics and Purespring Therapeutics. All other authors declare no competing interests.
Databáze: MEDLINE
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