Letter | Published:

Hippo pathway deficiency reverses systolic heart failure after infarction

Nature volume 550, pages 260264 (12 October 2017) | Download Citation



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 mortality1. The Hippo pathway, a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration2, 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.

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This work was supported by grants from the National Institutes of Health (DE023177, HL127717, HL130804, HL118761 (J.F.M.); F31HL136065 (M.C.H.) and 5T32HL007676-23 (J.P.L.)), Vivian L. Smith Foundation (J.F.M.), State of Texas funding (J.F.M. and J.T.W.), LeDucq Foundation Transatlantic Networks of Excellence in Cardiovascular Research (14CVD01) ‘Defining the genomic topology of atrial fibrillation’ (J.F.M.). Supported by Intellectual and Developmental Disabilities Research Center grant number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development and the Mouse Phenotyping Core at Baylor College of Medicine (U54 HG006348). T.H. was supported by American Heart Association Scientist Development Grant (16SDG26460001). This work was also supported in part by Neuroconnectivity core and Optical Imaging and Vital Microscopy core at Baylor College of Medicine. N. Stancel provided editorial assistance.

Author information


  1. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA

    • John P. Leach
    • , Min Zhang
    •  & James F. Martin
  2. The Texas Heart Institute, 6770 Bertner Avenue, Houston, Texas 77030, USA

    • Todd Heallen
    • , Mahdis Rahmani
    • , Yuka Morikawa
    • , Ana Segura
    • , James T. Willerson
    •  & James F. Martin
  3. Shanghai Children’s Medical Center, Shanghai 200127, China

    • Min Zhang
  4. Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA

    • Matthew C. Hill
    •  & James F. Martin
  5. Cardiovascular Research Institute, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA

    • James F. Martin


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J.P.L., J.T.W., and J.F.M. conceived and designed experiments and interpreted data. J.P.L., T.H., M.Z., M.C.H., Y.M., and M.R. performed experiments. J.P.L. and J.F.M. analysed data and compiled figures. A.S. provided human tissue samples J.P.L., J.T.W., and J.F.M. wrote and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to James F. Martin.

Reviewer Information Nature thanks M. Schneider and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    Supplementary Information

    This file contains Supplementary Figure 1 and Supplementary Table 1. Supplementary Figure 1 shows the uncropped scans with size marker indications and Supplementary Table 1 shows a list of qPCR primers.

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