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Nature. 2017 Oct 12;550(7675):260-264. doi: 10.1038/nature24045. Epub 2017 Oct 4.

Hippo pathway deficiency reverses systolic heart failure after infarction.

Author information

1
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
2
The Texas Heart Institute, 6770 Bertner Avenue, Houston, Texas 77030, USA.
3
Shanghai Children's Medical Center, Shanghai 200127, China.
4
Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
5
Cardiovascular Research Institute, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

Abstract

Mammalian organs vary widely in regenerative capacity. Poorly regenerative organs, such as the heart are particularly vulnerable to organ failure. Once established, heart failure commonly results in mortality. The Hippo pathway, a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration, is upregulated in human heart failure. Here we show that deletion of the Hippo pathway component Salvador (Salv) in mouse hearts with established ischaemic heart failure after myocardial infarction induces a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function compared with controls. Using translating ribosomal affinity purification, we isolate cardiomyocyte-specific translating messenger RNA. Hippo-deficient cardiomyocytes have increased expression of proliferative genes and stress response genes, such as the mitochondrial quality control gene, Park2. Genetic studies indicate that Park2 is essential for heart repair, suggesting a requirement for mitochondrial quality control in regenerating myocardium. Gene therapy with a virus encoding Salv short hairpin RNA improves heart function when delivered at the time of infarct or after ischaemic heart failure following myocardial infarction was established. Our findings indicate that the failing heart has a previously unrecognized reparative capacity involving more than cardiomyocyte renewal.

PMID:
28976966
PMCID:
PMC5729743
DOI:
10.1038/nature24045
[Indexed for MEDLINE]
Free PMC Article

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