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Histone methyltransferase Smyd3 is a new regulator for vascular senescence.

ABSTRACT: Endothelial cell senescence is one of the main risk factors contributing to vascular diseases. As increasing number of "epigenetic drugs" entering clinical trials, understanding the mechanism of epigenetic regulation in vascular aging has significant implications in finding targets to cure vascular diseases. However, the epigenetic regulation of endothelial senescence remains unclear. Based on the findings that increased protein level of histone H3 lysine 4 (H3K4) methyltransferase Smyd3 and elevated H3K4me3 modification happened in angiotensin II (Ang II)-induced senescence in rat endothelial cells, we are curious about whether and how Smyd3 can regulate endothelial senescence. We found that an increase of Smyd3 alone promoted senescence-associated phenotypes, while knockdown of Smyd3 blocked senescence in endothelial cells. Furthermore, Smyd3-specific inhibitor reversed vascular senescence-associated phenotypes at cellular level. Importantly, Ang II-induced vascular senescence can be greatly alleviated in Smyd3 knockout (KO) mice and those treated with Smyd3 inhibitor. Mechanistically, Smyd3 directly bound to the promoter region of Cdkn1a (coding for p21), then caused its increased H3K4me3 level and elevated gene expression, and ultimately gave rise to senescence-associated phenotypes. Intriguingly, Smyd3-mediated p21 upregulated expression also exists in human tissues of vascular disease, indicating it is probably an evolutionarily conserved mechanism in regulating vascular senescence. Thus, Smyd3 can act as a novel factor regulating endothelial senescence through transcriptionally promoting p21 expression. Blocking the Smyd3-p21 signaling axis may also have potential medical implications in treating diseases related to vascular aging.

SUBMITTER: Yang D

PROVIDER: S-EPMC7511874 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Histone methyltransferase Smyd3 is a new regulator for vascular senescence.

Yang Di D Wei Gang G Long Fen F Nie Hongbo H Tian Xiaoli X Qu Lefeng L Wang ShuangXi S Li Peng P Qiu Yue Y Wang Yang Y Hong Wanjin W Ni Ting T Liu Xinhua X Zhu Yi Zhun YZ

Aging cell 20200811 9

Endothelial cell senescence is one of the main risk factors contributing to vascular diseases. As increasing number of "epigenetic drugs" entering clinical trials, understanding the mechanism of epigenetic regulation in vascular aging has significant implications in finding targets to cure vascular diseases. However, the epigenetic regulation of endothelial senescence remains unclear. Based on the findings that increased protein level of histone H3 lysine 4 (H3K4) methyltransferase Smyd3 and ele ...[more]

PMID: 32779886

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Project description:Abstract Background In obesity, adipose tissue undergoes a remodeling process characterized by increased adipocyte size (hypertrophia) and number (hyperplasia). The individual ability to tip the balance toward the hyperplastic growth, with recruitment of new fat cells through adipogenesis, seems to be critical for a healthy adipose tissue expansion, as opposed to the development of inflammation and detrimental metabolic consequences. However, the molecular mechanisms underlying this fine-tuned regulation are far from being understood. Methods We analyzed by mass spectrometry-based proteomics visceral white adipose tissue (vWAT) samples collected from C57BL6 mice fed with a HFD for 8 weeks. A subset of these mice, called low responders (LowR HFD), showed a low susceptibility to the onset of adipose tissue inflammation, as opposed to their HFD counterpart. We identified the discriminants between LowR HFD and HFD vWAT samples and explored their function in Adipose Derived human Mesenchymal Stem Cells (AD-hMSCs) differentiated to adipocytes. Results We quantified 6051 proteins. Among the candidates that most differentiate LowR HFD from HFD vWAT, we found proteins involved in adipocyte function, including adiponectin and hormone sensitive lipase, suggesting that adipocyte differentiation is enhanced in LowR HFD, as compared to HFD. The chromatin modifier SET and MYND Domain Containing 3 (SMYD3), whose function in adipose tissue was totally unknown, was another top-scored hit. SMYD3 expression was significantly higher in LowR HFD vWAT, as confirmed by western blot analysis. In vitro, we found that SMYD3 mRNA and protein levels decrease rapidly along the differentiation process of AD-hMSCs. Moreover, SMYD3 knock-down at the beginning of adipocyte differentiation resulted in reduced cell proliferation and, at longer term, reduced lipid accumulation in adipocytes. Conclusions Our study describes for the first time the role of SMYD3 as a regulator of adipocyte proliferation during the early steps of adipogenesis.

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Histone methyltransferase Smyd3 is a new regulator for vascular senescence.

Publications

Histone methyltransferase Smyd3 is a new regulator for vascular senescence.

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