Transient overexpression of hPKM2 in porcine cardiomyocytes prevents heart failure after myocardial infarction
The adult mammalian heart lacks the ability to regenerate after injury, contributing to heart failure. No current treatment reactivates heart muscle cell division to prevent this decline. We used a targeted, non-viral modified mRNA system to transiently boost expression of a regenerative enzyme, pyruvate kinase muscle isozyme M2, in heart muscle cells of juvenile and adult pig models after ischemic injury. In juvenile pigs treated one-week post-injury, we observed increased markers of cell division, secretion of protective factors, improved heart function, and reduced scarring two months later. In adult pigs treated immediately after injury, we saw improved heart contractility and less fibrosis one month later. These results show that targeted pyruvate kinase muscle isozyme M2 modified mRNA delivery can stimulate muscle regeneration and functional recovery in both young and adult pig hearts. This approach offers a promising strategy for repairing ischemic injury and preventing heart failure in humans.
Authors
- Yu Lu (ORCID: https://orcid.org/0000-0002-2516-4031)
- Gregory P. Walcott (ORCID: https://orcid.org/0000-0002-9807-7422)
- Gayatri Mainkar (ORCID: https://orcid.org/0009-0009-5931-5035)
- Jianyi Zhang (ORCID: https://orcid.org/0000-0002-3955-6554)
- Magdalena M. Żak (ORCID: https://orcid.org/0000-0002-8625-7274)
- Yalin Wu (ORCID: https://orcid.org/0000-0001-5906-5675)
- Hesham A. Sadek (ORCID: https://orcid.org/0000-0002-4745-366X)
- Harry T. Lawless
- Lior Zangi (ORCID: https://orcid.org/0000-0002-6153-9857)
- Jimeen Yoo (ORCID: https://orcid.org/0000-0001-9283-3963)
- Patrick Soon‐Shiong (ORCID: https://orcid.org/0000-0002-4682-8298)
- Matthew Adjmi
- Jiacheng Sun (ORCID: https://orcid.org/0000-0001-5289-3451)
- Ann Kurian (ORCID: https://orcid.org/0000-0002-6058-3581)
- Rachel C. Matthews (ORCID: https://orcid.org/0000-0002-7339-2207)
Institutions
- University of Arizona (US)
- Wilmington University (US)
- University of Alabama at Birmingham (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-24
- DOI
- https://doi.org/10.1038/s41467-025-65344-4
- Citations
- 1
- Primary Topic
- Congenital heart defects research
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- American Heart Association
- National Institutes of Health