GSK126 an inhibitor of epigenetic regulator EZH2 suppresses cardiac fibrosis by regulating the<i>EZH2-PAX6-CXCL10</i>pathway

Aziz, Shireen; Li, Yalan; Raza, Muhammad Haseeb; Jiao, Lemin; Akram, Hafiz Muhammad Bilal; Zhao, Wen

doi:10.1139/bcb-2022-0224

Cited by 7 publications

(3 citation statements)

References 45 publications

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“…Besides, GSK 126 treatment diminished the upregulated expression of fibrosis-related proteins in NRCFs cultured with high glucose. This was consistent with a recent study, in which GSK126 could reverse ISO-induced myocardial fibrosis [ 28 ]. In summary, our research demonstrated that CaN/NFATc3 played a crucial role in the process of myocardial fibrosis induced by diabetes.…”

Section: Discussionsupporting

confidence: 94%

Calcineurin/NFATc3 pathway mediates myocardial fibrosis in diabetes by impairing enhancer of zeste homolog 2 of cardiac fibroblasts

Zhang,

Liu,

Yang

et al. 2023

BMC Cardiovasc Disord

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Background Diabetes is associated with myocardial fibrosis, while the underlying mechanisms remain elusive. The aim of this study is to investigate the underlying role of calcineurin/nuclear factor of activated T cell 3 (CaN/NFATc3) pathway and the Enhancer of zeste homolog 2 (EZH2) in diabetes-related myocardial fibrosis. Methods Streptozotocin (STZ)-injected diabetic rats were randomized to two groups: the controlled glucose (Con) group and the diabetes mellitus (DM) group. Eight weeks later, transthoracic echocardiography was used for cardiac function evaluation, and myocardial fibrosis was visualized by Masson trichrome staining. The primary neonatal rat cardiac fibroblasts were cultured with high-glucose medium with or without cyclosporine A or GSK126. The expression of proteins involved in the pathway was examined by western blotting. The nuclear translocation of target proteins was assessed by immunofluorescence. Results The results indicated that high glucose treatment increased the expression of CaN, NFATc3, EZH2 and trimethylates lysine 27 on histone 3 (H3K27me3) in vitro and in vivo. The inhibition of the CaN/NFATc3 pathway alleviated myocardial fibrosis. Notably, inhibition of CaN can inhibit the nuclear translocation of NFATc3, and the expression of EZH2 and H3K27me3 protein induced by high glucose. Moreover, treatment with GSK126 also ameliorated myocardial fibrosis. Conclusion Diabetes can possibly promote myocardial fibrosis by activating of CaN/NFATc3/EZH2 pathway.

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Section: Discussionsupporting

confidence: 94%

Calcineurin/NFATc3 pathway mediates myocardial fibrosis in diabetes by impairing enhancer of zeste homolog 2 of cardiac fibroblasts

Zhang,

Liu,

Yang

et al. 2023

BMC Cardiovasc Disord

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“…Additionally, YFV prompts monocytes and macrophages to release a deluge of pro-inflammatory mediators, like IL-6, IL-2, and TNF-α, inciting a ‘cytokine storm’ where the severity of heart failure correlates with the level of inflammatory factors [ 43 ]. CXCL10, upregulated by YFV infection, further aggravates cardiac hypertrophy and insufficiency [ 44 ]. Hemorrhagic fever, a hallmark of YFV-induced cardiovascular disease, arises from capillary damage and plasma leakage.…”

Section: Flaviviridae Viruses and Cardiovascular Diseasementioning

confidence: 99%

A Review on The Pathogenesis of Cardiovascular Disease of Flaviviridea Viruses Infection

Yang,

Gao,

et al. 2024

Viruses

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Members of the Flaviviridae family, encompassing the Flavivirus and Hepacivirus genera, are implicated in a spectrum of severe human pathologies. These diseases span a diverse spectrum, including hepatitis, vascular shock syndrome, encephalitis, acute flaccid paralysis, and adverse fetal outcomes, such as congenital heart defects and increased mortality rates. Notably, infections by Flaviviridae viruses have been associated with substantial cardiovascular compromise, yet the exploration into the attendant cardiovascular sequelae and underlying mechanisms remains relatively underexplored. This review aims to explore the epidemiology of Flaviviridae virus infections and synthesize their cardiovascular morbidities. Leveraging current research trajectories and our investigative contributions, we aspire to construct a cogent theoretical framework elucidating the pathogenesis of Flaviviridae-induced cardiovascular injury and illuminate prospective therapeutic avenues.

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“…On the one hand, a reduced expression of EZH2, and therefore of H3K27me3 levels, has been associated with the induction of pro-fibrotic genes in the skin and the heart [ 80 , 81 , 82 ]. On the other hand, a pro-fibrotic role for EZH2 has been described in liver, lung, and heart fibrotic diseases [ 83 , 84 , 85 , 86 ]. In addition, the demethylation of the histone mark H3K9me2 governed by KDM3a has been shown to cause fibrosis in a mouse model of pressure overload.…”

Section: Epigenetics In Cardiac Fibrosismentioning

confidence: 99%

Fibroblast Diversity and Epigenetic Regulation in Cardiac Fibrosis

Aguado-Alvaro,

Garitano,

Pelacho

2024

IJMS

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Cardiac fibrosis, a process characterized by excessive extracellular matrix (ECM) deposition, is a common pathological consequence of many cardiovascular diseases (CVDs) normally resulting in organ failure and death. Cardiac fibroblasts (CFs) play an essential role in deleterious cardiac remodeling and dysfunction. In response to injury, quiescent CFs become activated and adopt a collagen-secreting phenotype highly contributing to cardiac fibrosis. In recent years, studies have been focused on the exploration of molecular and cellular mechanisms implicated in the activation process of CFs, which allow the development of novel therapeutic approaches for the treatment of cardiac fibrosis. Transcriptomic analyses using single-cell RNA sequencing (RNA-seq) have helped to elucidate the high cellular diversity and complex intercellular communication networks that CFs establish in the mammalian heart. Furthermore, a significant body of work supports the critical role of epigenetic regulation on the expression of genes involved in the pathogenesis of cardiac fibrosis. The study of epigenetic mechanisms, including DNA methylation, histone modification, and chromatin remodeling, has provided more insights into CF activation and fibrotic processes. Targeting epigenetic regulators, especially DNA methyltransferases (DNMT), histone acetylases (HAT), or histone deacetylases (HDAC), has emerged as a promising approach for the development of novel anti-fibrotic therapies. This review focuses on recent transcriptomic advances regarding CF diversity and molecular and epigenetic mechanisms that modulate the activation process of CFs and their possible clinical applications for the treatment of cardiac fibrosis.

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GSK126 an inhibitor of epigenetic regulator EZH2 suppresses cardiac fibrosis by regulating theEZH2-PAX6-CXCL10pathway

Cited by 7 publications

References 45 publications

Calcineurin/NFATc3 pathway mediates myocardial fibrosis in diabetes by impairing enhancer of zeste homolog 2 of cardiac fibroblasts

Calcineurin/NFATc3 pathway mediates myocardial fibrosis in diabetes by impairing enhancer of zeste homolog 2 of cardiac fibroblasts

A Review on The Pathogenesis of Cardiovascular Disease of Flaviviridea Viruses Infection

Fibroblast Diversity and Epigenetic Regulation in Cardiac Fibrosis

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