Cardiac-Specific YAP Activation Improves Cardiac Function and Survival in an Experimental Murine MI Model
Open accessAbstract
Rationale : Yes-associated protein (YAP), the terminal effector of the Hippo signaling pathway, is crucial for regulating embryonic cardiomyocyte proliferation. Objective : We hypothesized that YAP activation after myocardial infarction (MI) would preserve cardiac function and improve survival. Methods and Results : We used a cardiac-specific, inducible expression system to activate YAP in adult mouse heart. Activation of YAP in adult heart promoted cardiomyocyte proliferation and did not deleteriously affect heart function. Furthermore, YAP activation after MI preserved heart function and reduced infarct size. Using adeno-associated virus subtype 9 (AAV9) as a delivery vector, we expressed human YAP (hYAP) in the adult murine myocardium immediately after MI. We found that AAV9:hYAP significantly improved cardiac function and mouse survival. AAV9:hYAP did not exert its salutary effects by reducing cardiomyocyte apoptosis. Rather, AAV9:hYAP stimulated adult cardiomyocyte proliferation. Gene expression profiling indicated that AAV9:hYAP stimulated expression of cell cycle genes and promoted a less mature cardiac gene expression signature. Conclusions : Cardiac-specific YAP activation after MI mitigated myocardial injury, improved cardiac function, and enhanced survival. These findings suggest that therapeutic activation of YAP or its downstream targets, potentially through AAV-mediated gene therapy, may be a strategy to improve outcome after MI.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In a mouse model of myocardial infarction, forcing human YAP expression in the heart via adeno-associated virus delivery increases cardiomyocyte proliferation and improves cardiac function and survival.
“Finally, in a mouse model of myocardial infarction, forcing human YAP expression in the heart using adeno-associated virus delivery increases cardiomyocyte proliferation and improves cardiac function as well as survival (85).”
From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as [85]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
TEAD mediates YAP-dependent gene induction and growth control
Zhao, B., Ye, X., Yu, J., Li, L., Li, W., Li, S., Yu, J., Lin, J. D., Wang, C.-Y., Chinnaiyan, A. M., et al. (2008) · Genes & Development · doi:10.1101/gad.1664408 · Cited by 2,498 · see citing works
Elucidation of a universal size-control mechanism in Drosophila and mammals
Dong, J., Feldmann, G., Huang, J., Wu, S., Zhang, N., Comerford, S. A., Gayyed, M. F., Anders, R. A., Maitra, A., & Pan, D. (2007) · Cell · doi:10.1016/j.cell.2007.07.019 · Cited by 2,370 · see citing works
Snippert, H. J., van der Flier, L. G., Sato, T., van Es, J. H., van den Born, M., Kroon-Veenboer, C., Barker, N., Klein, A. M., van Rheenen, J., Simons, B. D., et al. (2010) · Cell · doi:10.1016/j.cell.2010.09.016 · Cited by 1,951 · see citing works
Analysis of AAV Serotypes 1–9 Mediated Gene Expression and Tropism in Mice After Systemic Injection
Zincarelli, C., Soltys, S., Rengo, G., & Rabinowitz, J. E. (2008) · Molecular Therapy · doi:10.1038/mt.2008.76 · Cited by 1,490 · see citing works
YAP1 increases organ size and expands undifferentiated progenitor cells
Camargo, F. D., Gokhale, S., Johnnidis, J. B., Fu, D., Bell, G. W., Jaenisch, R., & Brummelkamp, T. R. (2007) · Current Biology · doi:10.1016/j.cub.2007.10.039 · Cited by 1,252 · see citing works
The Hippo–YAP pathway in organ size control and tumorigenesis: an updated versionPreprint
Zhao, B., Li, L., Lei, Q., & Guan, K. (2010) · Genes & Development · doi:10.1101/gad.1909210 · Cited by 1,140 · see citing works
Hippo Pathway Inhibits Wnt Signaling to Restrain Cardiomyocyte Proliferation and Heart Size
Heallen, T. R., Zhang, M., Wang, J., Bonilla-Claudio, M., Klysik, E., Johnson, R. L., & Martin, J. F. (2011) · Science · doi:10.1126/science.1199010 · Cited by 1,092 · see citing works
Yap1 acts downstream of α-catenin to control epidermal proliferation
Schlegelmilch, K., Mohseni, M., Kirak, O., Pruszak, J., Rodriguez, J. R., Zhou, D., Kreger, B. T., Vasioukhin, V., Avruch, J., Brummelkamp, T. R., et al. (2011) · Cell · doi:10.1016/j.cell.2011.02.031 · Cited by 1,036 · see citing works
Neuregulin1/ErbB4 Signaling Induces Cardiomyocyte Proliferation and Repair of Heart Injury
Bersell, K. R., Arab, S., Haring, B., & Kühn, B. (2009) · Cell · doi:10.1016/j.cell.2009.04.060 · Cited by 1,023 · see citing works
Gene therapy using adeno-associated virus vectors
Daya, S., & Berns, K. I. (2008) · Clinical Microbiology Reviews · doi:10.1128/cmr.00008-08 · Cited by 926 · see citing works
Hippo pathway effector Yap promotes cardiac regeneration
Xin, M., Kim, Y., Sutherland, L. B., Murakami, M., Qi, X., McAnally, J., Porrello, E. R., Mahmoud, A. I., Tan, W., Shelton, J. M., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1313192110 · Cited by 895 · see citing works
Macrophages are required for adult salamander limb regeneration
Godwin, J. W., Pinto, A. R., & Rosenthal, N. A. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1300290110 · Cited by 829 · see citing works
Macrophages are required for neonatal heart regeneration
Aurora, A. B., Porrello, E. R., Tan, W. H., Mahmoud, A. I., Hill, J. A., Bassel‐Duby, R., Sadek, H. A., & Olson, E. N. (2014) · Journal of Clinical Investigation · doi:10.1172/jci72181 · Cited by 823 · see citing works
von Gise, A., Lin, Z., Schlegelmilch, K., Honor, L. B., Pan, G. M., Buck, J. N., Ma, Q., Ishiwata, T., Zhou, B., Camargo, F. D., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1116136109 · Cited by 573 · see citing works
Self-citationProduction and characterization of adeno-associated viral vectors
Grieger, J. C., Choi, V. W., & Samulski, R. J. (2006) · Nature Protocols · doi:10.1038/nprot.2006.207 · Cited by 567 · see citing works
Xin, M., Kim, Y., Sutherland, L. B., Qi, X., McAnally, J., Schwartz, R. J., Richardson, J. A., Bassel‐Duby, R., & Olson, E. N. (2011) · Science Signaling · doi:10.1126/scisignal.2002278 · Cited by 549 · see citing works
Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2
Maejima, Y., Kyoi, S., Zhai, P., Liu, T., Li, H., Ivessa, A., Sciarretta, S., Del Re, D. P., Zablocki, D. K., Hsu, C.-P., et al. (2013) · Nature Medicine · doi:10.1038/nm.3322 · Cited by 499 · see citing works
Hippo signaling impedes adult heart regeneration
Heallen, T., Morikawa, Y., Leach, J., Tao, G., Willerson, J. T., Johnson, R. L., & Martin, J. F. (2013) · Development · doi:10.1242/dev.102798 · Cited by 458 · see citing works
Pasumarthi, K. B. S., Nakajima, H., Nakajima, H. O., Soonpaa, M. H., & Field, L. J. (2004) · Circulation Research · doi:10.1161/01.res.0000152326.91223.4f · Cited by 345 · see citing works
Yamamoto, S., Yang, G., Zablocki, D. K., Liu, J., Hong, C., Kim, S.-J., Soler, S., Odashima, M. M., Thaisz, J., Yehia, G., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17459 · Cited by 306 · see citing works
Oh, H., Taffet, G. E., Youker, K. A., Entman, M. L., Overbeek, P. A., Michael, L. H., & Schneider, M. D. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.191169098 · Cited by 289 · see citing works
Chen, S. N., Gurha, P., Lombardi, R., Ruggiero, A., Willerson, J. T., & Marian, A. J. (2014) · Circulation Research · doi:10.1161/circresaha.114.302810 · Cited by 275 · see citing works
YAP and TAZ Regulate Skin Wound Healing
Lee, M.-J., Byun, M. R., Furutani‐Seiki, M., Hong, J., & Jung, H.-S. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2013.339 · Cited by 257 · see citing works
Clonally dominant cardiomyocytes direct heart morphogenesis
Gupta, V., & Poss, K. D. (2012) · Nature · doi:10.1038/nature11045 · Cited by 255 · see citing works
Apoptotic versus autophagic cell death in heart failure
Knaapen, M. W. M., Davies, M. J., De Bie, M., Haven, A. J., Martinet, W., & Kockx, M. M. (2001) · Cardiovascular Research · doi:10.1016/s0008-6363(01)00290-5 · Cited by 233 · see citing works
C/EBP Transcription Factors Mediate Epicardial Activation During Heart Development and Injury
Huang, G. N., Thatcher, J. E., McAnally, J., Kong, Y., Qi, X., Tan, W. H., DiMaio, J. M., Amatruda, J. F., Gerard, R. D., Hill, J. A., et al. (2012) · Science · doi:10.1126/science.1229765 · Cited by 217 · see citing works
Targeting inflammatory pathways in myocardial infarction
Christia, P., & Frangogiannis, N. G. (2013) · European Journal of Clinical Investigation · doi:10.1111/eci.12118 · Cited by 207 · see citing works
Anillin localization defect in cardiomyocyte binucleation
Engel, F. B., Schebesta, M., & Keating, M. T. (2006) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2006.06.012 · Cited by 154 · see citing works
Lats2 Is a Negative Regulator of Myocyte Size in the Heart
Matsui, Y., Nakano, N., Shao, D., Gao, S., Luo, W., Hong, C., Zhai, P., Holle, E., Yu, X., Yabuta, N., et al. (2008) · Circulation Research · doi:10.1161/circresaha.108.180042 · Cited by 133 · see citing works
Gabriel, A. S., Martinsson, A., Wretlind, B., & Ahnve, S. (2004) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2004.07.013 · Cited by 124 · see citing works
Control of mitochondrial structure and function by the Yorkie/YAP oncogenic pathwayPreprint
Nagaraj, R., Rao, S. G., Jones, K. T., Slattery, M. G., Negre, N. N., Braas, D., Christofk, H. R., White, K. P., Mann, R. S., & Banerjee, U. K. (2012) · Genes & Development · doi:10.1101/gad.183061.111 · Cited by 102 · see citing works
TWEAK is a positive regulator of cardiomyocyte proliferation
Novoyatleva, T., Diehl, F., van Amerongen, M. J., Patra, C., Ferrazzi, F., Bellazzi, R., & Engel, F. B. (2009) · Cardiovascular Research · doi:10.1093/cvr/cvp360 · Cited by 97 · see citing works
Remodeling and dedifferentiation of adult cardiomyocytes during disease and regeneration
Szibor, M., Pöling, J., Warnecke, H., Kubin, T., & Braun, T. W. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1535-6 · Cited by 81 · see citing works
Muscle : fundamental biology and mechanisms of disease
Hill, J. A., Olson, E. N., Griendling, K. K., Kitsis, R. N., Stull, J. T., & Sweeney, H. L. (2012) · Cited by 76 · see citing works
Kaspar, B. K., Roth, D. M., Chin Lai, N., Drumm, J. D., Erickson, D. A., McKirnan, M. D., & Hammond, H. K. (2005) · The Journal of Gene Medicine · doi:10.1002/jgm.665 · Cited by 59 · see citing works
Mammalian Myocardial Regeneration
Zhou, B., Lin, Z., & Pu, W. T. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-381510-1.00039-9 · Cited by 6 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Hippo pathway in organ size control, tissue homeostasis, and cancer
Yu, F.-X., Zhao, B., & Guan, K.-L. (2015) · Cell · doi:10.1016/j.cell.2015.10.044 · Cited by 2,206 · see citing works
Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine
Dey, A., Varelas, X., & Guan, K.-L. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0070-z · Cited by 860 · see citing works
A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice
Tian, Y., Liu, Y., Wang, T., Zhou, N., Kong, J., Chen, L., Snitow, M., Morley, M., Li, D., Petrenko, N., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.3010841 · Cited by 381 · see citing works
Mills, R. J., Parker, B. L., Quaife-Ryan, G. A., Voges, H. K., Needham, E. J., Bornot, A., Ding, M., Andersson, H., Polla, M., Elliott, D. A., et al. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2019.03.009 · Cited by 312 · see citing works
mRNA-Based Protein Replacement Therapy for the Heart
Magadum, A., Kaur, K., & Zangi, L. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2018.11.018 · Cited by 176 · see citing works
View from the heart: cardiac fibroblasts in development, scarring and regeneration
Furtado, M. B., Nim, H. T., Boyd, S. E., & Rosenthal, N. A. (2016) · Development · doi:10.1242/dev.120576 · Cited by 144 · see citing works
Später, D., Hansson, E. M., Zangi, L., & Chien, K. R. (2014) · Development · doi:10.1242/dev.091538 · Cited by 143 · see citing works
Delivery of modified mRNA to damaged myocardium by systemic administration of lipid nanoparticles
Evers, M. J. W., Du, W., Yang, Q., Kooijmans, S. A. A., Vink, A., van Steenbergen, M., Vader, P., de Jager, S. C. A., Fuchs, S. A., Mastrobattista, E., et al. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.01.027 · Cited by 113 · see citing works
miRNAs that Induce Human Cardiomyocyte Proliferation Converge on the Hippo Pathway
Diez-Cuñado, M., Wei, K., Bushway, P. J., Maurya, M. R., Perera, R., Subramaniam, S., Ruiz-Lozano, P., & Mercola, M. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.04.049 · Cited by 102 · see citing works
Telomerase therapy attenuates cardiotoxic effects of doxorubicin
Chatterjee, S., Hofer, T., Costa, A., Lu, D., Batkai, S., Gupta, S. K., Bolesani, E., Zweigerdt, R., Megias, D., Streckfuss-Bömeke, K., et al. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2020.12.035 · Cited by 63 · see citing works
The Hippo signal transduction network for exercise physiologists
Gabriel, B. M., Hamilton, D. L., Tremblay, A. M., & Wackerhage, H. (2016) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01076.2015 · Cited by 48 · see citing works
- Authors
- Lin, Z., von Gise, A., Zhou, P., Gu, F., Ma, Q., Jiang, J., Yau, A. L., Buck, J. N., Gouin, K. A., van Gorp, P. R. R., Zhou, B., Chen, J., Seidman, J. G., Wang, D.-Z., & Pu, W. T.
- Affiliations
- Boston Children's Hospital (US)
- From the Departments of Cardiology, Boston Children’s Hospital (Z.L., A.v.G., P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W., W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA; Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z...
- ORCID
- Venue
- Circulation Research
- Published
- 2014-07-18
- Volume
- 115
- Issue
- 3
- Pages
- 354-363
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC4104149
- OpenAlex
- W2129466238
- Cited by
- 403
- References
- 36
- Citations by year
- 2026: 18 · 2025: 26 · 2024: 44 · 2023: 41 · 2022: 41 · 2021: 41 · 2020: 46 · 2019: 45 · 2018: 22 · 2017: 23 · 2016: 30 · 2015: 18 · 2014: 8
- FWCI
- 10.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Universiteit Leiden
- National Institutes of Health (5u01hl100401-07)
- National Heart, Lung, and Blood Institute (HL116461, HL100401, U01-HL-100401, R01HL116461)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- YAP, Hippo signaling pathway, myocardial infarction, cardiomyocyte proliferation, cardiac function, infarct size, AAV9 gene therapy, cardiac-specific gene expression, cell cycle genes, cardiomyocyte apoptosis
- MeSH terms
- YAP-Signaling Proteins, Dependovirus, Animals, Cell Survival, Disease Models, Animal, Cardiomegaly, Humans, Mice, Transgenic, Myocardial Contraction, Myocardial Infarction, Phosphoproteins, Regeneration, Transcription Factors, Survival Rate, Apoptosis, Myosin Heavy Chains, Myocytes, Cardiac, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
