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MYBPC3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis
Genetic mutations in the MYBPC3 gene encoding cardiac myosin binding protein C (cMyBP-C) are the most common cause of hypertrophic cardiomyopathy (HCM). Myocardial fibrosis (MF) plays a critical role in the development of HCM. However, the mechanism for mutant MYBPC3-induced MF is not well defined....
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9649783/ https://www.ncbi.nlm.nih.gov/pubmed/36357371 http://dx.doi.org/10.1038/s41419-022-05403-6 |
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author | Zou, Xiaodong Ouyang, Hongsheng Lin, Feng Zhang, Huanyu Yang, Yang Pang, Daxin Han, Renzhi Tang, Xiaochun |
author_facet | Zou, Xiaodong Ouyang, Hongsheng Lin, Feng Zhang, Huanyu Yang, Yang Pang, Daxin Han, Renzhi Tang, Xiaochun |
author_sort | Zou, Xiaodong |
collection | PubMed |
description | Genetic mutations in the MYBPC3 gene encoding cardiac myosin binding protein C (cMyBP-C) are the most common cause of hypertrophic cardiomyopathy (HCM). Myocardial fibrosis (MF) plays a critical role in the development of HCM. However, the mechanism for mutant MYBPC3-induced MF is not well defined. In this study, we developed a R495Q mutant pig model using cytosine base editing and observed an early-onset MF in these mutant pigs shortly after birth. Unexpectedly, we found that the “cardiac-specific” MYBPC3 gene was actually expressed in cardiac fibroblasts from different species as well as NIH3T3 fibroblasts at the transcription and protein levels. CRISPR-mediated disruption of Mybpc3 in NIH3T3 fibroblasts activated nuclear factor κB (NF-κB) signaling pathway, which increased the expression of transforming growth factor beta (TGF-β1) and other pro-inflammatory genes. The upregulation of TGF-β1 promoted the expression of hypoxia-inducible factor-1 subunit α (HIF-1α) and its downstream targets involved in glycolysis such as GLUT1, PFK, and LDHA. Consequently, the enhanced aerobic glycolysis with higher rate of ATP biosynthesis accelerated the activation of cardiac fibroblasts, contributing to the development of HCM. This work reveals an intrinsic role of MYBPC3 in maintaining cardiac fibroblast homeostasis and disruption of MYBPC3 in these cells contributes to the disease pathogenesis of HCM. |
format | Online Article Text |
id | pubmed-9649783 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-96497832022-11-15 MYBPC3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis Zou, Xiaodong Ouyang, Hongsheng Lin, Feng Zhang, Huanyu Yang, Yang Pang, Daxin Han, Renzhi Tang, Xiaochun Cell Death Dis Article Genetic mutations in the MYBPC3 gene encoding cardiac myosin binding protein C (cMyBP-C) are the most common cause of hypertrophic cardiomyopathy (HCM). Myocardial fibrosis (MF) plays a critical role in the development of HCM. However, the mechanism for mutant MYBPC3-induced MF is not well defined. In this study, we developed a R495Q mutant pig model using cytosine base editing and observed an early-onset MF in these mutant pigs shortly after birth. Unexpectedly, we found that the “cardiac-specific” MYBPC3 gene was actually expressed in cardiac fibroblasts from different species as well as NIH3T3 fibroblasts at the transcription and protein levels. CRISPR-mediated disruption of Mybpc3 in NIH3T3 fibroblasts activated nuclear factor κB (NF-κB) signaling pathway, which increased the expression of transforming growth factor beta (TGF-β1) and other pro-inflammatory genes. The upregulation of TGF-β1 promoted the expression of hypoxia-inducible factor-1 subunit α (HIF-1α) and its downstream targets involved in glycolysis such as GLUT1, PFK, and LDHA. Consequently, the enhanced aerobic glycolysis with higher rate of ATP biosynthesis accelerated the activation of cardiac fibroblasts, contributing to the development of HCM. This work reveals an intrinsic role of MYBPC3 in maintaining cardiac fibroblast homeostasis and disruption of MYBPC3 in these cells contributes to the disease pathogenesis of HCM. Nature Publishing Group UK 2022-11-10 /pmc/articles/PMC9649783/ /pubmed/36357371 http://dx.doi.org/10.1038/s41419-022-05403-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Zou, Xiaodong Ouyang, Hongsheng Lin, Feng Zhang, Huanyu Yang, Yang Pang, Daxin Han, Renzhi Tang, Xiaochun MYBPC3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis |
title | MYBPC3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis |
title_full | MYBPC3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis |
title_fullStr | MYBPC3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis |
title_full_unstemmed | MYBPC3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis |
title_short | MYBPC3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis |
title_sort | mybpc3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9649783/ https://www.ncbi.nlm.nih.gov/pubmed/36357371 http://dx.doi.org/10.1038/s41419-022-05403-6 |
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