Ezh2 Inhibits Replicative Senescence of Atrial Fibroblasts Through Promotion of H3K27me3 in the Promoter Regions of CDKN2a and Timp4 Genes
Yingze Li,* Guojian Fang,* Wei Cao,* Jiali Yuan,* Shuai Song, Hong Peng, Yuepeng Wang, Qunshan Wang Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, People’s Republic of China*These auth...
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Dove Medical Press
2022-08-01
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| Series: | Journal of Inflammation Research |
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| Online Access: | https://www.dovepress.com/ezh2-inhibits-replicative-senescence-of-atrial-fibroblasts-through-pro-peer-reviewed-fulltext-article-JIR |
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| author | Li Y Fang G Cao W Yuan J Song S Peng H Wang Y Wang Q |
| author_facet | Li Y Fang G Cao W Yuan J Song S Peng H Wang Y Wang Q |
| author_sort | Li Y |
| collection | DOAJ |
| description | Yingze Li,* Guojian Fang,* Wei Cao,* Jiali Yuan,* Shuai Song, Hong Peng, Yuepeng Wang, Qunshan Wang Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qunshan Wang; Yuepeng Wang, Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, People’s Republic of China, Email wangqunshan@xinhuamed.com.cn; wangyuepeng@xinhuamed.com.cnBackground: In most cell types, replicative senescence (RS) is supposed to be a principle causative factor for aging. Atrial fibrosis, pathologically characterized by proliferation of atrial fibroblasts (AFs) and excessive accumulation of extracellular matrix proteins, is the most common substrate of atrial fibrillation (Afib) in the elderly. However, whether AFs’ RS develops in the aged and fibrotic left atrium (LA) and, if yes, what is the key regulator for the pathogenesis of AFs’ RS remain largely unknown.Methods: We obtained the left atrial tissues from young (6– 8 weeks old) and aged (24 months old) C57BL/6 male mice. Screening and validation of differential genes were performed using comparative analysis of RNA-seq results. Replicative senescence was examined in primary AFs after cell passage. Further gain-of-function and loss-of-function experiments were performed to explore the regulation of the AFs’ RS progression.Results: In the present study, we demonstrated that there was a considerable extent of AFs’ RS in the aged and fibrotic LA. Transcriptome screening showed that Ezh2 (Enhancer of zeste homolog 2) was significantly downregulated in the LA tissue of aged mice. Ezh2 is a histone methyltransferase that catalyzes H3K27me3 and mediates transcriptional silencing. We confirmed that Ezh2 was downregulated in the isolated pure senescent AFs. Knockdown of Ezh2 by siRNA or inhibition of Ezh2ʹs methyltransferase activities by GSK-126 and GSK-343 accelerated RS in the early passage of AFs, while its overexpression deaccelerated RS in the late passage of AFs. Mechanistically, Ezh2 suppressed CDKN2a (p16, p19) and Timp4 gene transcription by forming canonical H3K27me3 modifications in their promoter regions. Furthermore, the functional balance between Timp4 and MMP8 in AFs could be collapsed by changes in Ezh2 expression.Conclusion: These results thus indicate that Ezh2 is a key regulator of AFs’ RS and this work may provide a basis for future treatments for atrial fibrosis in the elderly.Graphical Abstract: Keywords: aging, replicative senescence, atrial fibrosis, Ezh2, H3K27me3 |
| first_indexed | 2024-04-13T02:17:50Z |
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| language | English |
| last_indexed | 2024-04-13T02:17:50Z |
| publishDate | 2022-08-01 |
| publisher | Dove Medical Press |
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| series | Journal of Inflammation Research |
| spelling | doaj.art-3e0c570a406746bbace1c7f9f055b3a42022-12-22T03:07:05ZengDove Medical PressJournal of Inflammation Research1178-70312022-08-01Volume 154693470877424Ezh2 Inhibits Replicative Senescence of Atrial Fibroblasts Through Promotion of H3K27me3 in the Promoter Regions of CDKN2a and Timp4 GenesLi YFang GCao WYuan JSong SPeng HWang YWang QYingze Li,* Guojian Fang,* Wei Cao,* Jiali Yuan,* Shuai Song, Hong Peng, Yuepeng Wang, Qunshan Wang Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qunshan Wang; Yuepeng Wang, Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, People’s Republic of China, Email wangqunshan@xinhuamed.com.cn; wangyuepeng@xinhuamed.com.cnBackground: In most cell types, replicative senescence (RS) is supposed to be a principle causative factor for aging. Atrial fibrosis, pathologically characterized by proliferation of atrial fibroblasts (AFs) and excessive accumulation of extracellular matrix proteins, is the most common substrate of atrial fibrillation (Afib) in the elderly. However, whether AFs’ RS develops in the aged and fibrotic left atrium (LA) and, if yes, what is the key regulator for the pathogenesis of AFs’ RS remain largely unknown.Methods: We obtained the left atrial tissues from young (6– 8 weeks old) and aged (24 months old) C57BL/6 male mice. Screening and validation of differential genes were performed using comparative analysis of RNA-seq results. Replicative senescence was examined in primary AFs after cell passage. Further gain-of-function and loss-of-function experiments were performed to explore the regulation of the AFs’ RS progression.Results: In the present study, we demonstrated that there was a considerable extent of AFs’ RS in the aged and fibrotic LA. Transcriptome screening showed that Ezh2 (Enhancer of zeste homolog 2) was significantly downregulated in the LA tissue of aged mice. Ezh2 is a histone methyltransferase that catalyzes H3K27me3 and mediates transcriptional silencing. We confirmed that Ezh2 was downregulated in the isolated pure senescent AFs. Knockdown of Ezh2 by siRNA or inhibition of Ezh2ʹs methyltransferase activities by GSK-126 and GSK-343 accelerated RS in the early passage of AFs, while its overexpression deaccelerated RS in the late passage of AFs. Mechanistically, Ezh2 suppressed CDKN2a (p16, p19) and Timp4 gene transcription by forming canonical H3K27me3 modifications in their promoter regions. Furthermore, the functional balance between Timp4 and MMP8 in AFs could be collapsed by changes in Ezh2 expression.Conclusion: These results thus indicate that Ezh2 is a key regulator of AFs’ RS and this work may provide a basis for future treatments for atrial fibrosis in the elderly.Graphical Abstract: Keywords: aging, replicative senescence, atrial fibrosis, Ezh2, H3K27me3https://www.dovepress.com/ezh2-inhibits-replicative-senescence-of-atrial-fibroblasts-through-pro-peer-reviewed-fulltext-article-JIRagingreplicative senescenceatrial fibrosisezh2h3k27me3 |
| spellingShingle | Li Y Fang G Cao W Yuan J Song S Peng H Wang Y Wang Q Ezh2 Inhibits Replicative Senescence of Atrial Fibroblasts Through Promotion of H3K27me3 in the Promoter Regions of CDKN2a and Timp4 Genes Journal of Inflammation Research aging replicative senescence atrial fibrosis ezh2 h3k27me3 |
| title | Ezh2 Inhibits Replicative Senescence of Atrial Fibroblasts Through Promotion of H3K27me3 in the Promoter Regions of CDKN2a and Timp4 Genes |
| title_full | Ezh2 Inhibits Replicative Senescence of Atrial Fibroblasts Through Promotion of H3K27me3 in the Promoter Regions of CDKN2a and Timp4 Genes |
| title_fullStr | Ezh2 Inhibits Replicative Senescence of Atrial Fibroblasts Through Promotion of H3K27me3 in the Promoter Regions of CDKN2a and Timp4 Genes |
| title_full_unstemmed | Ezh2 Inhibits Replicative Senescence of Atrial Fibroblasts Through Promotion of H3K27me3 in the Promoter Regions of CDKN2a and Timp4 Genes |
| title_short | Ezh2 Inhibits Replicative Senescence of Atrial Fibroblasts Through Promotion of H3K27me3 in the Promoter Regions of CDKN2a and Timp4 Genes |
| title_sort | ezh2 inhibits replicative senescence of atrial fibroblasts through promotion of h3k27me3 in the promoter regions of cdkn2a and timp4 genes |
| topic | aging replicative senescence atrial fibrosis ezh2 h3k27me3 |
| url | https://www.dovepress.com/ezh2-inhibits-replicative-senescence-of-atrial-fibroblasts-through-pro-peer-reviewed-fulltext-article-JIR |
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