βIV-Spectrin/STAT3 complex regulates fibroblast phenotype, fibrosis, and cardiac function

Patel, Nehal; Nassal, Drew; Greer-Short, Amara; Unudurthi, Sathya D.; Scandling, Benjamin W; Gratz, Daniel; Xu, Xianyao; Kalyanasundaram, Anuradha; Fedorov, Vadim V.; Accornero, Federica; Mohler, Peter J.; Gooch, Keith J.; Hund, Thomas J.

doi:10.1172/jci.insight.131046

Cited by 19 publications

(28 citation statements)

References 45 publications

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“…6a). Furthermore, through literature research, we found that 9 MYC target genes were previously reported involving the development of heart failure, including STAT3 [48], PRMT1 [49], PRKCH [50], HSPA4 [51], DDX3X [52], GYG1 [53], GADD45B [54] and PKN1 [55] (Fig. 6a, the red ones).…”

Section: The Myc and C/ebpβ Mediated Transcriptional Networkmentioning

confidence: 74%

Identification of transcription factors MYC and C/EBPβ mediated regulatory networks in heart failure

Wang

et al. 2019

Preprint

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Background: Heart failure is one of leading cause of death worldwide. However, the transcriptional profiling of heart failure is unclear. Moreover, the signaling pathways and transcription factors involving the heart failure developmental progress also are largely unclear.Methods: The transcriptional profiling of heart failure was identified from integrated gene expression datasets. The enriched pathways and transcription factors were analyzed using DAVID and GSEA assay. The transcriptional networks were created by Cytoscape.Results: Compared with the normal heart tissues, we found 90 genes were particularly differentially expressed in heart failing tissues, and those genes were associated with multiple metabolism pathways and insulin signaling pathway. Metabolism and insulin signaling pathway were both inactivated in heart failing tissues. Transcription factors MYC and C/EBPβ were both negatively associated with the expression profiling of heart failing tissues in GSEA assay. Moreover, compared with normal heart tissues, MYC and C/EBPβ were down regulated in heart failing tissues. Furthermore, MYC and C/EBPβ mediated downstream target genes were decreased in heart failing tissues. MYC and C/EBPβ were positively correlated with each other. At last, we constructed the transcription factor MYC and C/EBPβ mediated regulatory networks in heart failing tissues, and identified the MYC and C/EBPβ target genes which had been reported involving the failure developmental progress by literature research. Conclusions: Our results suggested that transcription factor MYC and C/EBPβ played critical roles in heart failure developmental progress. And new heart failure treatments may be developed by targeting MYC and C/EBPβ.

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Section: The Myc and C/ebpβ Mediated Transcriptional Networkmentioning

confidence: 74%

Identification of transcription factors MYC and C/EBPβ mediated regulatory networks in heart failure

Wang

et al. 2019

Preprint

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show abstract

“…7a). Furthermore, through literature research, we found that some MYC target genes were previously reported involving the development of heart failure, including STAT3 [30], PRMT1 [31], PRKCH [32] and HSPA4 [33] (Fig. 7a).…”

Section: The Myc and C/ebpβ Mediated Transcriptional Networkmentioning

confidence: 81%

Identification of transcription factors MYC and C/EBPβ mediated regulatory networks in heart failure based on gene expression omnibus datasets

Wang

et al. 2020

BMC Cardiovasc Disord

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Background: Heart failure is one of leading cause of death worldwide. However, the transcriptional profiling of heart failure is unclear. Moreover, the signaling pathways and transcription factors involving the heart failure development also are largely unknown. Using published Gene Expression Omnibus (GEO) datasets, in the present study, we aim to comprehensively analyze the differentially expressed genes in failing heart tissues, and identified the critical signaling pathways and transcription factors involving heart failure development. Methods: The transcriptional profiling of heart failure was identified from previously published gene expression datasets deposited in GSE5406, GSE16499 and GSE68316. The enriched signaling pathways and transcription factors were analyzed using Database for Annotation, Visualization and Integrated Discovery (DAVID) website and gene set enrichment analysis (GSEA) assay. The transcriptional networks were created by Cytoscape. Results: Compared with the normal heart tissues, 90 genes were particularly differentially expressed in failing heart tissues, and those genes were associated with multiple metabolism signaling pathways and insulin signaling pathway. Metabolism and insulin signaling pathway were both inactivated in failing heart tissues. Transcription factors MYC and C/EBPβ were both negatively associated with the expression profiling of failing heart tissues in GSEA assay. Moreover, compared with normal heart tissues, MYC and C/EBPβ were down regulated in failing heart tissues. Furthermore, MYC and C/EBPβ mediated downstream target genes were also decreased in failing heart tissues. MYC and C/EBPβ were positively correlated with each other. At last, we constructed MYC and C/EBPβ mediated regulatory networks in failing heart tissues, and identified the MYC and C/EBPβ target genes which had been reported involving the heart failure developmental progress. Conclusions: Our results suggested that metabolism pathways and insulin signaling pathway, transcription factors MYC and C/EBPβ played critical roles in heart failure developmental progress.

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“…A mouse model with ßIV-spectrin mutant mice has shown impaired cardiac function through different mechanisms, involving ßIV-spectrin ( 10 , 11 ). Myocytes of SPTBN4 mutant mice have shown highly eccentric myocyte growth ( 11 ).…”

Section: Discussionmentioning

confidence: 99%

“…Another model with ßIV-spectrin mutant mice has shown impaired cardiac function through the activation of cardiac fibrosis. ßIV-spectrin binds the transcription factor STAT3, a transcriptional regulator influencing cell responses like hypertrophy and proliferation ( 11 ). Loss of ßIV-spectrin results in impaired binding of STAT3 leading to its activation.…”

Section: Introductionmentioning

confidence: 99%

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Severe Form of ßIV-Spectrin Deficiency With Mitochondrial Dysfunction and Cardiomyopathy—A Case Report

et al. 2021

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ßIV-spectrin is a protein of the spectrin family which is involved in the organization of the cytoskeleton structure and is found in high quantity in the axon initial segment and the nodes of Ranvier. Together with ankyrin G, ßIV-spectrin is responsible for the clustering of KCNQ2/3-potassium channels and NaV-sodium channels. Loss or reduction of ßIV-spectrin causes a destabilization of the cytoskeleton and an impairment in the generation of the action potential, which leads to neuronal degeneration. Furthermore, ßIV-spectrin has been described to play an important role in the maintenance of the neuronal polarity and of the diffusion barrier. ßIV-spectrin is also located in the heart where it takes an important part in the structural organization of ion channels and has also been described to participate in cell signaling pathways through binding of transcription factors. We describe two patients with a severe form of ßIV-spectrin deficiency. Whole-exome sequencing revealed the homozygous stop mutation c.6016C>T (p.R2006*) in the SPTBN4 gene. The phenotype of these patients is characterized by profound psychomotor developmental arrest, respiratory insufficiency and deafness. Additionally one of the patients presents with cardiomyopathy, optical nerve atrophy, and mitochondrial dysfunction. This is the first report of a severe form of ßIV-spectrin deficiency with hypertrophic cardiomyopathy and mitochondrial dysfunction.

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βIV-Spectrin/STAT3 complex regulates fibroblast phenotype, fibrosis, and cardiac function

Cited by 19 publications

References 45 publications

Identification of transcription factors MYC and C/EBPβ mediated regulatory networks in heart failure

Identification of transcription factors MYC and C/EBPβ mediated regulatory networks in heart failure

Identification of transcription factors MYC and C/EBPβ mediated regulatory networks in heart failure based on gene expression omnibus datasets

Severe Form of ßIV-Spectrin Deficiency With Mitochondrial Dysfunction and Cardiomyopathy—A Case Report

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