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

Nat Cardiovasc Res. 2024 Mar;3(3):372-388. doi: 10.1038/s44161-024-00450-y. Epub 2024 Mar 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Proliferation* / drug effects
  • Cells, Cultured
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Drug Approval
  • Homeodomain Proteins* / genetics
  • Homeodomain Proteins* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Ecotropic Viral Integration Site 1 Protein* / genetics
  • Myeloid Ecotropic Viral Integration Site 1 Protein* / metabolism
  • Myocardial Reperfusion Injury / drug therapy
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / pathology
  • Myocytes, Cardiac* / drug effects
  • Myocytes, Cardiac* / metabolism
  • Neomycin / pharmacology
  • Rats
  • Regeneration* / drug effects
  • Swine
  • Transcription, Genetic / drug effects
  • United States
  • United States Food and Drug Administration
  • Ventricular Function, Left / drug effects

Substances

  • Homeodomain Proteins
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Neomycin
  • Meis1 protein, mouse