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High levels of glucose induce “metabolic memory” in cardiomyocyte via epigenetic histone H3 lysine 9 methylation

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Abstract

Diabetic patients continue to develop inflammation and cardiovascular complication even after achieving glycemic control, suggesting a “metabolic memory”. Metabolic memory is a major challenge in the treatment of diabetic complication, and the mechanisms underlying metabolic memory are not clear. Recent studies suggest a link between chromatin histone methylation and metabolic memory. In this study, we tested whether histone 3 lysine-9 tri-methylation (H3K9me3), a key epigenetic chromatin marker, was involved in high glucose (HG)-induced inflammation and metabolic memory. Incubating cardiomyocyte cells in HG resulted in increased levels of inflammatory cytokine IL-6 mRNA when compared with myocytes incubated in normal culture media, whereas mannitol (osmotic control) has no effect. Chromatin immunoprecipitation (ChIP) assays showed that H3K9me3 levels were significantly decreased at the promoters of IL-6. Immunoblotting demonstrated that protein levels of the H3K9me3 methyltransferase, Suv39h1, were also reduced after HG treatment. HG-induced apoptosis, mitochondrial dysfunction and cytochrome-c release were reversible. However, the effects of HG on the expression of IL-6 and the levels of H3K9me3 were irreversible after the removal of HG from the culture. These results suggest that HG-induced sustained inflammatory phenotype and epigenetic histone modification, rather than HG-induced mitochondrial dysfunction and apoptosis, are main mechanisms responsible for metabolic memory. In conclusion, our data demonstrate that HG increases expression of inflammatory cytokine and decreases the levels of histone-3 methylation at the cytokine promoter, and suggest that modulating histone 3 methylation and inflammatory cytokine expression may be a useful strategy to prevent metabolic memory and cardiomyopathy in diabetic patients.

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Acknowledgments

This work was supported by American Heart Association (0765149Y to Y. Li), the MacDonald Foundation (10RDM009 and 07RDM008 to Y. Li), and National Natural Science Foundation of China (Nos. 81070103 and 81120108003 to X.Y.Yu).

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Authors and Affiliations

  1. Texas Heart Institute, University of Texas Health Science Center, 6770 Bertner Avenue, Houston, TX, 77030, USA

    Yong-Jian Geng & Yangxin Li

  2. Guangdong Provincial Cardiovascular Institute, Medical Research Center, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, People’s Republic of China

    Xi-Yong Yu, Jia-Liang Liang, He-Ping Lei, Shi-Long Zhong, Qiu-Xiong Lin, Zhi-Xin Shan & Shu-Guang Lin

  3. Section of Cardiology, Xiangya Hospital of Central-South University, Changsha, 410008, Hunan, People’s Republic of China

    Saidan Zhang

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  1. Xi-Yong Yu
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  4. Saidan Zhang
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  9. Shu-Guang Lin
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  10. Yangxin Li
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Correspondence to Yangxin Li.

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Xi-Yong Yu and Yangxin Li contributed equally to this work.

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Yu, XY., Geng, YJ., Liang, JL. et al. High levels of glucose induce “metabolic memory” in cardiomyocyte via epigenetic histone H3 lysine 9 methylation. Mol Biol Rep 39, 8891–8898 (2012). https://doi.org/10.1007/s11033-012-1756-z

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  • DOI: https://doi.org/10.1007/s11033-012-1756-z

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