Mitochondrial gene COX2 methylation and downregulation is a biomarker of aging in heart mesenchymal stem cells

Sun,Xiguang; Wang,Zilong; Cong,Xiaoqiang; Lv,Yudan; Li,Zhuo; Rong,Li; Yang,Tianye; Yu,Dehai

doi:10.3892/ijmm.2020.4799

Mitochondrial gene COX2 methylation and downregulation is a biomarker of aging in heart mesenchymal stem cells

Authors:
- Xiguang Sun
- Zilong Wang
- Xiaoqiang Cong
- Yudan Lv
- Zhuo Li
- Li Rong
- Tianye Yang
- Dehai Yu
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Affiliations: Department of Hand Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China, Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China, Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China, Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China, Department of Plastic and Reconstructive Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China, Laboratory of Cancer Precision Medicine, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
Published online on: November 25, 2020 https://doi.org/10.3892/ijmm.2020.4799
Pages: 161-170
Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The mitochondria have been proven to be involved in processes of aging; however, the mechansims through which mitoepigenetics affect the cytological behaviors of cardiomyocytes during the aging process are not yet fully understood. In the present study, two senescence models were constructed, replicative senescence (RS) and stress‑induced premature senescence (SIPS), using human heart mesenchymal stem cells (HMSCs). First, the differences in age‑related gene expression levels and telomere length were compared between the HMSCs in the RS and SIPS models by PCR. Subsequently, protein expression and the mitochondrial DNA (mtDNA) methylation status of cytochrome c oxidase subunit II (COX2) was measured by western blot analysis and bisulfite genomic sequencing (BSP). Finally, the value of the DNA methyltransferase (Dnmt) inhibitor, 5‑aza‑2'‑deoxycytidine (AdC), in delaying the senescence of HMSCs was evaluated. It was found that the p16, p27 and p53 mRNA expression levels increased in the senescent cells, whereas p21 mRNA expression did not. It was also found that telomere shortening only occurred in the RS model, but not in the SIPS model. Along with the senescence of HMSCs, COX2 gene methylation increased and its protein expression level significantly decreased. It was demonstrated that AdC inhibited COX2 methylation and downregulated COX2 expression. The addition of exogenous COX2 or the administration of AdC promoted cell proliferation and delayed cell aging. On the whole, the present study demonstrates that COX2 methylation and downregulation are biomarkers of HMSC senescence. Thus, COX2 may have potential for use as a therapeutic target of cardiovascular diseases and this warrants further investigation.

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