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The Hippo Pathway Is Activated and Is a Causal Mechanism for Adipogenesis in Arrhythmogenic Cardiomyopathy
Open accessAbstract
RATIONALE: Mutations in the intercalated disc proteins, such as plakophilin 2 (PKP2), cause arrhythmogenic cardiomyopathy (AC). AC is characterized by the replacement of cardiac myocytes by fibro-adipocytes, cardiac dysfunction, arrhythmias, and sudden death. OBJECTIVE: To delineate the molecular pathogenesis of AC. METHODS AND RESULTS: Localization and levels of selected intercalated disc proteins, including signaling molecules, were markedly reduced in human hearts with AC. Altered protein constituents of intercalated discs were associated with activation of the upstream Hippo molecules in the human hearts, in Nkx2.5-Cre:Dsp(W/F) and Myh6:Jup mouse models of AC, and in the PKP2 knockdown HL-1 myocytes (HL-1(PKP2:shRNA)). Level of active protein kinase C-α isoform, which requires PKP2 for activity, was reduced. In contrast, neurofibromin 2 (or Merlin), a molecule upstream of the Hippo pathway and that is inactivated by protein kinase C-α isoform, was activated. Consequently, the downstream Hippo molecules mammalian STE20-like protein kinases 1/2 (MST1/2), large tumor suppressor kinases 1/2 (LATS1/2), and Yes-associated protein (YAP) (the latter is the effector of the pathway) were phosphorylated. Coimmunoprecipitation detected binding of phosphorylated YAP, phosphorylated β-catenin, and junction protein plakoglobin (the latter translocated from the junction). RNA sequencing, transcript quantitative polymerase chain reaction, and reporter assays showed suppressed activity of SV40 transcriptional enhancer factor domain (TEAD) and transcription factor 7-like 2 (TCF7L2), which are transcription factors of the Hippo and the canonical Wnt signaling, respectively. In contrast, adipogenesis was enhanced. Simultaneous knockdown of Lats1/2, molecules upstream to YAP, rescued inactivation of YAP and β-catenin and adipogenesis in the HL-1(PKP2:shRNA) myocytes. CONCLUSIONS: Molecular remodeling of the intercalated discs leads to pathogenic activation of the Hippo pathway, suppression of the canonical Wnt signaling, and enhanced adipogenesis in AC. The findings offer novel mechanisms for the pathogenesis of AC.
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“In a landmark study by Garcia-Gras E et al. [77], these authors demonstrated that suppression of canonical Wnt/β-catenin signaling leads to ACM, prominently through competition with nuclear localization of JUP, rather than through β-catenin degradation [77,79,80].”
From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [79]
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“The loss of nuclear YAP in conjunction with Wnt/β-catenin suppression further drives adipogenesis and maladaptive fibrotic repair [79,80].”
From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [79]
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“Conversely, in ACM, prior studies have demonstrated aberrant Hippo pathway activation and subsequent YAP inactivation [79].”
From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [79]
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“Recent evidence implicates fibro-adipogenic progenitors and epicardial-derived cells as primary sources, and they typically show an epicardial to endocardial migration [77,79,83,84].”
From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [79]
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Wnt/β-catenin signaling and disease
Clevers, H., & Nusse, R. (2012) · Cell · doi:10.1016/j.cell.2012.05.012 · Cited by 5,554
Marcus, F. I., McKenna, W. J., Sherrill, D., Basso, C., Bauce, B., Bluemke, D. A., Calkins, H., Corrado, D., Cox, M. G. P. J., Daubert, J. P., et al. (2010) · Circulation · doi:10.1161/circulationaha.108.840827 · Cited by 2,676
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Marcus, G. M., McKenna, W. J., Sherrill, D., Basso, C., Bauce, B., Bluemke, D. A., Calkins, H. G., Corrado, D., Cox, M. G. P. J., Daubert, J. P., et al. (2010) · European Heart Journal · doi:10.1093/eurheartj/ehq025 · Cited by 1,610
The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal
Zhao, B., Tumaneng, K., & Guan, K.-L. (2011) · Nature Cell Biology · doi:10.1038/ncb2303 · Cited by 1,205
Phosphate-binding Tag, a New Tool to Visualize Phosphorylated Proteins
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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
Corrado, D., Basso, C., Thiene, G., McKenna, W. J., Davies, M. J., Fontaliran, F., Nava, A., Silvestri, F., Blomstrom-Lundqvist, C., Wlodarska, E. K., et al. (1997) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(97)00332-x · Cited by 978
Arrhythmogenic right ventricular cardiomyopathy
Basso, C., Corrado, D., Marcus, G. M., Nava, A. K., & Thiene, G. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60256-7 · Cited by 938
Research works printed but not linked: 1
- 10.1128/MCB.13.9.5206 · DOI
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The Hippo Pathway: Biology and Pathophysiology
Ma, S., Meng, Z., Chen, R., & Guan, K.-L. (2019) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-013118-111829 · Cited by 1,387
The Hippo Signaling Pathway in Development and Disease
Zheng, Y., & Pan, D. (2019) · Developmental Cell · doi:10.1016/j.devcel.2019.06.003 · Cited by 867
Towbin, J. A., McKenna, W. J., Abrams, D. J., Ackerman, M. J., Calkins, H. G., Darrieux, F., Daubert, J. P., de Chillou, C., DePasquale, E. C., Desai, M. Y., et al. (2019) · Heart Rhythm · doi:10.1016/j.hrthm.2019.05.007 · Cited by 883
The Hippo signalling pathway and its implications in human health and diseases
Fu, M., Hu, Y., Lan, T., Guan, K., Luo, T., & Luo, M. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01191-9 · Cited by 823
Cardiomyocyte Maturation: New Phase in Development
Guo, Y., & Pu, W. T. (2020) · Circulation Research · doi:10.1161/circresaha.119.315862 · Cited by 653
Metadata
- Authors
- Chen, S. N., Gurha, P., Lombardi, R., Ruggiero, A., Willerson, J. T., & Marian, A. J.
- Affiliations
- The University of Texas Health Science Center at Houston (US)
- Venue
- Circulation Research
- Published
- 2014-01-31
- Volume
- 114
- Issue
- 3
- Pages
- 454-468
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC3946717
- OpenAlex
- W2170939446
- Cited by
- 275
- References
- 62
- Citations by year
- 2026: 14 · 2025: 23 · 2024: 11 · 2023: 24 · 2022: 21 · 2021: 34 · 2020: 20 · 2019: 21 · 2018: 22 · 2017: 32 · 2016: 17 · 2015: 21 · 2014: 15
- FWCI
- 10.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R21AG038597)
- National Heart, Lung, and Blood Institute (R34HL105563, R01HL088498)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
- Keywords
- arrhythmogenic cardiomyopathy, Hippo signaling pathway, adipogenesis, plakophilin-2, intercalated discs, protein kinase C alpha, Merlin, YAP, MST1/2, LATS1/2, Wnt/β-catenin signaling, β-catenin, plakoglobin
- MeSH terms
- Hippo Signaling Pathway, Animals, Cell Line, Humans, Signal Transduction, Protein Serine-Threonine Kinases, Mice, Knockout, Arrhythmogenic Right Ventricular Dysplasia, Adipogenesis, Mice
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