Hippo Deficiency Leads to Cardiac Dysfunction Accompanied by Cardiomyocyte De-Differentiation During Pressure Overload
| Autor: | Peiyong Zhai, Michinari Nakamura, Lai-Hua Xie, Dae-Sik Lim, Mohit Kumar, Sakthivel Sadayappan, Shin Ichi Oka, Bin Tian, Hiroaki Shimokawa, Dominic P. Del Re, Sebastiano Sciarretta, Chiao Po Hsu, Risa Mukai, Maha Abdellatif, Ji Yeon Park, Shohei Ikeda, Nadezhda Fefelova, Junichi Sadoshima, Iain K. Farrance, Wataru Mizushima |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Physiology apoptosis cell cycle cell proliferation heart failure mice physiology cardiology and cardiovascular medicine Apoptosis Cell Cycle Proteins Oncostatin M 030204 cardiovascular system & hematology Protein Serine-Threonine Kinases Article Ventricular Function Left 03 medical and health sciences Ventricular Dysfunction Left 0302 clinical medicine Medicine Animals Hippo Signaling Pathway Myocytes Cardiac Rats Wistar Cells Cultured Adaptor Proteins Signal Transducing Pressure overload Heart Failure Mice Knockout Hippo signaling pathway Cell growth business.industry fungi Cell Cycle TEA Domain Transcription Factors YAP-Signaling Proteins Organ Size Cell cycle Cell Dedifferentiation medicine.disease Phosphoproteins Cell biology DNA-Binding Proteins Mice Inbred C57BL Disease Models Animal 030104 developmental biology Heart failure Signal transduction Cardiology and Cardiovascular Medicine business Signal Transduction Transcription Factors |
| Popis: | Rationale: The Hippo pathway plays an important role in determining organ size through regulation of cell proliferation and apoptosis. Hippo inactivation and consequent activation of YAP (Yes-associated protein), a transcription cofactor, have been proposed as a strategy to promote myocardial regeneration after myocardial infarction. However, the long-term effects of Hippo deficiency on cardiac function under stress remain unknown. Objective: We investigated the long-term effect of Hippo deficiency on cardiac function in the presence of pressure overload (PO). Methods and Results: We used mice with cardiac-specific homozygous knockout of WW45 (WW45cKO), in which activation of Mst1 (Mammalian sterile 20-like 1) and Lats2 (large tumor suppressor kinase 2), the upstream kinases of the Hippo pathway, is effectively suppressed because of the absence of the scaffolding protein. We used male mice at 3 to 4 month of age in all animal experiments. We subjected WW45cKO mice to transverse aortic constriction for up to 12 weeks. WW45cKO mice exhibited higher levels of nuclear YAP in cardiomyocytes during PO. Unexpectedly, the progression of cardiac dysfunction induced by PO was exacerbated in WW45cKO mice, despite decreased apoptosis and activated cardiomyocyte cell cycle reentry. WW45cKO mice exhibited cardiomyocyte sarcomere disarray and upregulation of TEAD1 (transcriptional enhancer factor) target genes involved in cardiomyocyte dedifferentiation during PO. Genetic and pharmacological inactivation of the YAP-TEAD1 pathway reduced the PO-induced cardiac dysfunction in WW45cKO mice and attenuated cardiomyocyte dedifferentiation. Furthermore, the YAP-TEAD1 pathway upregulated OSM (oncostatin M) and OSM receptors, which played an essential role in mediating cardiomyocyte dedifferentiation. OSM also upregulated YAP and TEAD1 and promoted cardiomyocyte dedifferentiation, indicating the existence of a positive feedback mechanism consisting of YAP, TEAD1, and OSM. Conclusions: Although activation of YAP promotes cardiomyocyte regeneration after cardiac injury, it induces cardiomyocyte dedifferentiation and heart failure in the long-term in the presence of PO through activation of the YAP-TEAD1-OSM positive feedback mechanism. |
| Databáze: | OpenAIRE |
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