Transient overexpression of hPKM2 in porcine cardiomyocytes prevents heart failure after myocardial infarction

Jiacheng Sun, Yalin Wu, Matthew Adjmi, Rachel C. Matthews, Ann Anu Kurian, Magdalena M. Żak, Jimeen Yoo, Gayatri Mainkar, Hannah Lawless, Yu-An Lu, Patrick Soon-Shiong, Gregory P. Walcott, Hesham A. Sadek, Jianyi Zhang () and Lior Zangi ()
Additional contact information
Jiacheng Sun: University of Alabama at Birmingham, Department of Biomedical Engineering, School of Medicine and School of Engineering
Yalin Wu: University of Alabama at Birmingham, Department of Biomedical Engineering, School of Medicine and School of Engineering
Matthew Adjmi: Icahn School of Medicine at Mount Sinai, Cardiovascular Research Center
Rachel C. Matthews: University of Alabama at Birmingham, Department of Biomedical Engineering, School of Medicine and School of Engineering
Ann Anu Kurian: Icahn School of Medicine at Mount Sinai, Cardiovascular Research Center
Magdalena M. Żak: Icahn School of Medicine at Mount Sinai, Cardiovascular Research Center
Jimeen Yoo: Icahn School of Medicine at Mount Sinai, Cardiovascular Research Center
Gayatri Mainkar: Icahn School of Medicine at Mount Sinai, Cardiovascular Research Center
Hannah Lawless: University of Alabama at Birmingham, Department of Biomedical Engineering, School of Medicine and School of Engineering
Yu-An Lu: University of Alabama at Birmingham, Department of Biomedical Engineering, School of Medicine and School of Engineering
Patrick Soon-Shiong: LLC, NantRNA
Gregory P. Walcott: University of Alabama at Birmingham, Division of Cardiovascular Diseases, Department of Medicine
Hesham A. Sadek: The University of Arizona College of Medicine, Division of Cardiology
Jianyi Zhang: University of Alabama at Birmingham, Department of Biomedical Engineering, School of Medicine and School of Engineering
Lior Zangi: Icahn School of Medicine at Mount Sinai, Cardiovascular Research Center

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65344-4

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