Letter | Published:

Hippo pathway deficiency reverses systolic heart failure after infarction

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

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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 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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References

  1. 1.

    , , , & Heart failure incidence and survival (from the Atherosclerosis Risk in Communities study). Am. J. Cardiol. 101, 1016–1022 (2008)

  2. 2.

    & Hippo signaling: growth control and beyond. Development 138, 9–22 (2011)

  3. 3.

    , , , & Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 367, 1747–1757 (2006)

  4. 4.

    & Treatment strategies for myocardial recovery in heart failure. Curr. Treat. Options Cardiovasc. Med. 16, 287 (2014)

  5. 5.

    Molecular changes after left ventricular assist device support for heart failure. Circ. Res. 113, 777–791 (2013)

  6. 6.

    Heart failure. JACC Heart Fail. 1, 1–20 (2013)

  7. 7.

    , & Transduction of mechanical and cytoskeletal cues by YAP and TAZ. Nat. Rev. Mol. Cell Biol. 13, 591–600 (2012)

  8. 8.

    et al. Hippo signaling impedes adult heart regeneration. Development 140, 4683–4690 (2013)

  9. 9.

    et al. Actin cytoskeletal remodeling with protrusion formation is essential for heart regeneration in Hippo-deficient mice. Sci. Signal. 8, ra41 (2015)

  10. 10.

    et al. Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury. Nature 534, 119–123 (2016)

  11. 11.

    et al. NF2 activates Hippo signaling and promotes ischemia/reperfusion injury in the heart. Circ. Res. 119, 596–606 (2016)

  12. 12.

    et al. Mst1 promotes cardiac myocyte apoptosis through phosphorylation and inhibition of Bcl-xL. Mol. Cell 54, 639–650 (2014)

  13. 13.

    , , , & Serial echocardiographic assessment of left ventricular dimensions and function after myocardial infarction in mice. Cardiovasc. Res. 45, 330–338 (2000)

  14. 14.

    et al. A single progenitor population switches behavior to maintain and repair esophageal epithelium. Science 337, 1091–1093 (2012)

  15. 15.

    Getting to the heart of the matter: new insights into cardiac fibrosis. Circ. Res. 116, 1269–1276 (2015)

  16. 16.

    , , & Platelet-derived growth factor D induces cardiac fibrosis and proliferation of vascular smooth muscle cells in heart-specific transgenic mice. Circ. Res. 97, 1036–1045 (2005)

  17. 17.

    & Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat. Rev. Mol. Cell Biol. 7, 589–600 (2006)

  18. 18.

    et al. Circulating biomarker responses to medical management vs. mechanical circulatory support in severe inotrope-dependent acute heart failure. ESC Heart Fail. 3, 86–96 (2016)

  19. 19.

    , , , & The cytoskeleton and related proteins in the human failing heart. Heart Fail. Rev. 5, 271–280 (2000)

  20. 20.

    , , & Epigenetic regulation in heart failure. Curr. Opin. Cardiol. 31, 255–265 (2016)

  21. 21.

    & Heart failure. N. Engl. J. Med. 348, 2007–2018 (2003)

  22. 22.

    & Mitochondrial dynamics and cell death in heart failure. Heart Fail. Rev. 21, 123–136 (2016)

  23. 23.

    . Parkin-dependent mitophagy in the heart. J. Mol. Cell. Cardiol. 95, 42–49 (2016)

  24. 24.

    et al. Parkin protein deficiency exacerbates cardiac injury and reduces survival following myocardial infarction. J. Biol. Chem. 288, 915–926 (2013)

  25. 25.

    et al. Hippo pathway effector Yap promotes cardiac regeneration. Proc. Natl Acad. Sci. USA 110, 13839–13844 (2013)

  26. 26.

    , , & Roles of FGF signals in heart development, health, and disease. Front. Cell Dev. Biol. 4, 110 (2016)

  27. 27.

    et al. Conditional transgenic expression of fibroblast growth factor 9 in the adult mouse heart reduces heart failure mortality after myocardial infarction. Circulation 123, 504–514 (2011)

  28. 28.

    , , & Fibroblast growth factor-9 enhances M2 macrophage differentiation and attenuates adverse cardiac remodeling in the infarcted diabetic heart. PLoS ONE 10, e0120739 (2015)

  29. 29.

    et al. Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice. Science 350, aad2459 (2015)

  30. 30.

    et al. Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration. Nat. Genet. 49, 1346–1353 (2017)

  31. 31.

    et al. Moderate and high amounts of tamoxifen in αMHC-MerCreMer mice induce a DNA damage response, leading to heart failure and death. Dis. Model. Mech. 6, 1459–1469 (2013)

  32. 32.

    et al. Avoidance of transient cardiomyopathy in cardiomyocyte-targeted tamoxifen-induced MerCreMer gene deletion models. Circ. Res. 105, 12–15 (2009)

  33. 33.

    , , , & Prolonged Cre expression driven by the α-myosin heavy chain promoter can be cardiotoxic. J. Mol. Cell. Cardiol. 86, 54–61 (2015)

  34. 34.

    et al. Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart. Am. J. Physiol. Heart Circ. Physiol. 279, H422–H428 (2000)

  35. 35.

    et al. A simple and fast experimental model of myocardial infarction in the mouse. Tex. Heart Inst. J. 33, 290–293 (2006)

  36. 36.

    et al. MIQuant – semi-automation of infarct size assessment in models of cardiac ischemic injury. PLoS ONE 6, e25045 (2011)

  37. 37.

    et al. Dynamics of cell generation and turnover in the human heart. Cell 161, 1566–1575 (2015)

  38. 38.

    et al. Cell-type-specific isolation of ribosome-associated mRNA from complex tissues. Proc. Natl Acad. Sci. USA 106, 13939–13944 (2009)

  39. 39.

    et al. Alternative splicing regulates vesicular trafficking genes in cardiomyocytes during postnatal heart development. Nat. Commun. 5, 3603 (2014)

  40. 40.

    et al. A pipeline for the generation of shRNA transgenic mice. Nat. Protocols 7, 374–393 (2012)

  41. 41.

    , , , & Dystrophin–glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation. Nature 547, 227–231 (2017)

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Acknowledgements

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

Affiliations

  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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Contributions

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.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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  1. 1.

    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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DOI

https://doi.org/10.1038/nature24045

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