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.
Similar content being viewed by others
References
Ihnat MA, Thorpe JE, Ceriello A (2007) Hypothesis: the ‘metabolic memory’, the new challenge of diabetes. Diabet Med 24:582–586
Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358:2560–5272
Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B (2005) Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353:2643–2653
Ceriello A, Ihnat MA, Thorpe JE (2009) Clinical review 2: the “metabolic memory”: is more than just tight glucose control necessary to prevent diabetic complications? J Clin Endocrinol Metab 94:410–415
Bird A (2007) Perceptions of epigenetics. Nature 447:396–398
Reik W (2007) Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447:425–432
Feinberg AP (2007) Phenotypic plasticity and the epigenetics of human disease. Nature 447:433–440
Noh H, Oh EY, Seo JY, Yu MR, Kim YO, Ha H, Lee HB (2009) Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta1-induced renal injury. Am J Physiol Renal Physiol 297:F729–F739
Reddy MA, Natarajan R (2011) Epigenetic mechanisms in diabetic vascular complications. Cardiovasc Res 90:421–429
Villeneuve LM, Natarajan R (2010) The role of epigenetics in the pathology of diabetic complications. Am J Physiol Renal Physiol 299:F14–F25
Li B, Carey M, Workman JL (2007) The role of chromatin during transcription. Cell 128:707–719
Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol 6:838–849
Margueron R, Reinberg D (2010) Chromatin structure and the inheritance of epigenetic information. Nat Rev Genet 11:285–296
Yu XY, Song YH, Geng YJ, Lin QX, Shan ZX, Lin SG, Li Y (2008) Glucose induces apoptosis of cardiomyocytes via microRNA-1 and IGF-1. Biochem Biophys Res Commun 376:548–552
Kuethe F, Sigusch HH, Bornstein SR, Hilbig K, Kamvissi V, Figulla HR (2007) Apoptosis in patients with dilated cardiomyopathy and diabetes: a feature of diabetic cardiomyopathy? Horm Metab Res 39:672–676
Chowdhry MF, Vohra HA, Galinanes M (2007) Diabetes increases apoptosis and necrosis in both ischemic and nonischemic human myocardium: role of caspases and poly-adenosine diphosphate-ribose polymerase. J Thorac Cardiovasc Surg 134:124–31, 131.e1–3
Cai L, Wang Y, Zhou G, Chen T, Song Y, Li X, Kang YJ (2006) Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy. J Am Coll Cardiol 48:1688–1697
Wang J, Song Y, Elsherif L, Song Z, Zhou G, Prabhu SD, Saari JT, Cai L (2006) Cardiac metallothionein induction plays the major role in the prevention of diabetic cardiomyopathy by zinc supplementation. Circulation 113:544–554
Chan PS, Kanwar M, Kowluru RA (2010) Resistance of retinal inflammatory mediators to suppress after reinstitution of good glycemic control: novel mechanism for metabolic memory. J Diabetes Complications 24:55–63
King GL (2008) The role of inflammatory cytokines in diabetes and its complications. J Periodontol 79:1527–1534
Devaraj S, Glaser N, Griffen S, Wang-Polagruto J, Miguelino E, Jialal I (2006) Increased monocytic activity and biomarkers of inflammation in patients with type 1 diabetes. Diabetes 55:774–779
Yu XY, Geng YJ, Liang JL, Lin QX, Lin SG, Zhang S, Li Y (2010) High levels of glucose induce apoptosis in cardiomyocyte via epigenetic regulation of the insulin-like growth factor receptor. Exp Cell Res 316:2903–2909
Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ (2002) Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes 51:1938–1948
Ho FM, Liu SH, Liau CS, Huang PJ, Lin-Shiau SY (2000) High glucose-induced apoptosis in human endothelial cells is mediated by sequential activations of c-Jun NH(2)-terminal kinase and caspase-3. Circulation 101:2618–2624
Rafty LA, Santiago FS, Khachigian LM (2002) NF1/X represses PDGF A-chain transcription by interacting with Sp1 and antagonizing Sp1 occupancy of the promoter. EMBO J 21:334–343
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).
Author information
Authors and Affiliations
Corresponding author
Additional information
Xi-Yong Yu and Yangxin Li contributed equally to this work.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-012-1756-z