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The epigenetic landscape in the cardiovascular complications of diabetes

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Abstract

A growing body of evidence suggests that epigenetic modifications—changes to the genome that do not involve changes in DNA sequence—may significantly derail transcriptional programs implicated in angiogenesis, oxidative stress and inflammation, thus fostering cardiovascular damage in patients with diabetes. Notably, adverse epigenetic signals acquired over the life course can be transmitted to the offspring, and may contribute to early cardiovascular phenotypes in the young generations. Hyperglycaemia and insulin resistance—key hallmarks of diabetes—induce an array of epigenetic modifications (i.e., DNA methylation, histone marks, and non-coding RNAs) which are responsible for a long-lasting impairment of vascular and cardiac function, even after intensive glycemic control. Hence, unveiling the “epigenetic landscape” in patients with diabetes may provide a post-genomic snapshot of global cardiovascular risk, and may furnish the tools to design personalized, epigenetic-based therapies to alleviate the burden of cardiovascular disease in diabetic patients. The present review aims to acquaint the scientific community with the rapidly advancing field of epigenetics and its implications in the cardiovascular complications of diabetes.

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References

  1. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M (1998) Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 339(4):229–234. https://doi.org/10.1056/NEJM199807233390404

    Article  CAS  PubMed  Google Scholar 

  2. Paneni F, Beckman JA, Creager MA, Cosentino F (2013) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur Heart J 34(31):2436–2443. https://doi.org/10.1093/eurheartj/eht149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Beckman JA, Paneni F, Cosentino F, Creager MA (2013) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part II. Eur Heart J 34(31):2444–2452. https://doi.org/10.1093/eurheartj/eht142

    Article  PubMed  Google Scholar 

  4. Low Wang CC, Hess CN, Hiatt WR, Goldfine AB (2016) Clinical update: cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus—mechanisms, management, and clinical considerations. Circulation 133(24):2459–2502. https://doi.org/10.1161/CIRCULATIONAHA.116.022194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ogurtsova K, da Rocha Fernandes JD, Huang Y, Linnenkamp U, Guariguata L, Cho NH, Cavan D, Shaw JE, Makaroff LE (2017) IDF diabetes atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract 128:40–50. https://doi.org/10.1016/j.diabres.2017.03.024

    Article  CAS  PubMed  Google Scholar 

  6. Baccarelli A, Rienstra M, Benjamin EJ (2010) Cardiovascular epigenetics: basic concepts and results from animal and human studies. Circ Cardiovasc Genet 3(6):567–573. https://doi.org/10.1161/CIRCGENETICS.110.958744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Handy DE, Castro R, Loscalzo J (2011) Epigenetic modifications: basic mechanisms and role in cardiovascular disease. Circulation 123(19):2145–2156. https://doi.org/10.1161/CIRCULATIONAHA.110.956839

    Article  PubMed  PubMed Central  Google Scholar 

  8. Brunet A, Berger SL (2014) Epigenetics of aging and aging-related disease. J Gerontol A Biol Sci Med Sci 69(Suppl 1):S17–S20. https://doi.org/10.1093/gerona/glu042

    Article  PubMed  PubMed Central  Google Scholar 

  9. Costantino S, Camici GG, Mohammed SA, Volpe M, Luscher TF, Paneni F (2018) Epigenetics and cardiovascular regenerative medicine in the elderly. Int J Cardiol 250:207–214. https://doi.org/10.1016/j.ijcard.2017.09.188

    Article  PubMed  Google Scholar 

  10. Benayoun BA, Pollina EA, Brunet A (2015) Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol 16(10):593–610. https://doi.org/10.1038/nrm4048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102(30):10604–10609. https://doi.org/10.1073/pnas.0500398102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Swygert SG, Peterson CL (2014) Chromatin dynamics: interplay between remodeling enzymes and histone modifications. Biochem Biophys Acta 1839(8):728–736. https://doi.org/10.1016/j.bbagrm.2014.02.013

    Article  CAS  PubMed  Google Scholar 

  13. Bohmdorfer G, Wierzbicki AT (2015) Control of chromatin structure by long noncoding RNA. Trends Cell Biol 25(10):623–632. https://doi.org/10.1016/j.tcb.2015.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Miranda TB, Jones PA (2007) DNA methylation: the nuts and bolts of repression. J Cell Physiol 213(2):384–390. https://doi.org/10.1002/jcp.21224

    Article  CAS  PubMed  Google Scholar 

  15. Subramaniam D, Thombre R, Dhar A, Anant S (2014) DNA methyltransferases: a novel target for prevention and therapy. Front Oncol 4:80. https://doi.org/10.3389/fonc.2014.00080

    Article  PubMed  PubMed Central  Google Scholar 

  16. Jenuwein T, Allis CD (2001) Translating the histone code. Science 293(5532):1074–1080. https://doi.org/10.1126/science.1063127

    Article  CAS  PubMed  Google Scholar 

  17. Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403(6765):41–45. https://doi.org/10.1038/47412

    Article  CAS  PubMed  Google Scholar 

  18. Eskeland R, Eberharter A, Imhof A (2007) HP1 binding to chromatin methylated at H3K9 is enhanced by auxiliary factors. Mol Cell Biol 27(2):453–465. https://doi.org/10.1128/MCB.01576-06

    Article  CAS  PubMed  Google Scholar 

  19. Thambirajah AA, Ng MK, Frehlick LJ, Li A, Serpa JJ, Petrotchenko EV, Silva-Moreno B, Missiaen KK, Borchers CH, Adam Hall J, Mackie R, Lutz F, Gowen BE, Hendzel M, Georgel PT, Ausio J (2012) MeCP2 binds to nucleosome free (linker DNA) regions and to H3K9/H3K27 methylated nucleosomes in the brain. Nucleic Acids Res 40(7):2884–2897. https://doi.org/10.1093/nar/gkr1066

    Article  CAS  PubMed  Google Scholar 

  20. Poller W, Dimmeler S, Heymans S, Zeller T, Haas J, Karakas M, Leistner DM, Jakob P, Nakagawa S, Blankenberg S, Engelhardt S, Thum T, Weber C, Meder B, Hajjar R, Landmesser U (2017) Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives. Eur Heart J. https://doi.org/10.1093/eurheartj/ehx165

    Article  PubMed Central  Google Scholar 

  21. Paneni F, Volpe M, Luscher TF, Cosentino F (2013) SIRT1, p66(Shc), and Set7/9 in vascular hyperglycemic memory: bringing all the strands together. Diabetes 62(6):1800–1807. https://doi.org/10.2337/db12-1648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, Lafont S, Bergeonneau C, Kassai B, Erpeldinger S, Wright JM, Gueyffier F, Cornu C (2011) Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ 343:d4169. https://doi.org/10.1136/bmj.d4169

    Article  PubMed  PubMed Central  Google Scholar 

  23. Castagno D, Baird-Gunning J, Jhund PS, Biondi-Zoccai G, MacDonald MR, Petrie MC, Gaita F, McMurray JJ (2011) Intensive glycemic control has no impact on the risk of heart failure in type 2 diabetic patients: evidence from a 37,229 patient meta-analysis. Am Heart J 162(5):938e932–948e932. https://doi.org/10.1016/j.ahj.2011.07.030

    Article  CAS  Google Scholar 

  24. Ceriello A (2009) Hypothesis: the “metabolic memory”, the new challenge of diabetes. Diabetes Res Clin Pract 86(Suppl 1):S2–S6. https://doi.org/10.1016/S0168-8227(09)70002-6

    Article  CAS  PubMed  Google Scholar 

  25. Ceriello A (2012) The emerging challenge in diabetes: the “metabolic memory”. Vascul Pharmacol 57(5–6):133–138. https://doi.org/10.1016/j.vph.2012.05.005

    Article  CAS  PubMed  Google Scholar 

  26. Park LK, Maione AG, Smith A, Gerami-Naini B, Iyer LK, Mooney DJ, Veves A, Garlick JA (2014) Genome-wide DNA methylation analysis identifies a metabolic memory profile in patient-derived diabetic foot ulcer fibroblasts. Epigenetics 9(10):1339–1349. https://doi.org/10.4161/15592294.2014.967584

    Article  PubMed  PubMed Central  Google Scholar 

  27. Paneni F, Mocharla P, Akhmedov A, Costantino S, Osto E, Volpe M, Luscher TF, Cosentino F (2012) Gene silencing of the mitochondrial adaptor p66(Shc) suppresses vascular hyperglycemic memory in diabetes. Circ Res 111(3):278–289. https://doi.org/10.1161/CIRCRESAHA.112.266593

    Article  CAS  PubMed  Google Scholar 

  28. Costantino S, Paneni F, Battista R, Castello L, Capretti G, Chiandotto S, Tanese L, Russo G, Pitocco D, Lanza GA, Volpe M, Luscher TF, Cosentino F (2017) Impact of glycemic variability on chromatin remodeling, oxidative stress, and endothelial dysfunction in patients with type 2 diabetes and with target HbA1c Levels. Diabetes 66(9):2472–2482. https://doi.org/10.2337/db17-0294

    Article  CAS  PubMed  Google Scholar 

  29. Zheng Z, Chen H, Li J, Li T, Zheng B, Zheng Y, Jin H, He Y, Gu Q, Xu X (2012) Sirtuin 1-mediated cellular metabolic memory of high glucose via the LKB1/AMPK/ROS pathway and therapeutic effects of metformin. Diabetes 61(1):217–228. https://doi.org/10.2337/db11-0416

    Article  CAS  PubMed  Google Scholar 

  30. Zhou S, Chen HZ, Wan YZ, Zhang QJ, Wei YS, Huang S, Liu JJ, Lu YB, Zhang ZQ, Yang RF, Zhang R, Cai H, Liu DP, Liang CC (2011) Repression of P66Shc expression by SIRT1 contributes to the prevention of hyperglycemia-induced endothelial dysfunction. Circ Res 109(6):639–648. https://doi.org/10.1161/CIRCRESAHA.111.243592

    Article  CAS  PubMed  Google Scholar 

  31. Orimo M, Minamino T, Miyauchi H, Tateno K, Okada S, Moriya J, Komuro I (2009) Protective role of SIRT1 in diabetic vascular dysfunction. Arterioscler Thromb Vasc Biol 29(6):889–894. https://doi.org/10.1161/ATVBAHA.109.185694

    Article  CAS  PubMed  Google Scholar 

  32. Albiero M, Poncina N, Tjwa M, Ciciliot S, Menegazzo L, Ceolotto G, Vigili de Kreutzenberg S, Moura R, Giorgio M, Pelicci P, Avogaro A, Fadini GP (2014) Diabetes causes bone marrow autonomic neuropathy and impairs stem cell mobilization via dysregulated p66Shc and Sirt1. Diabetes 63(4):1353–1365. https://doi.org/10.2337/db13-0894

    Article  CAS  PubMed  Google Scholar 

  33. Villeneuve LM, Reddy MA, Lanting LL, Wang M, Meng L, Natarajan R (2008) Epigenetic histone H3 lysine 9 methylation in metabolic memory and inflammatory phenotype of vascular smooth muscle cells in diabetes. Proc Natl Acad Sci USA 105(26):9047–9052. https://doi.org/10.1073/pnas.0803623105

    Article  PubMed  PubMed Central  Google Scholar 

  34. Okabe J, Orlowski C, Balcerczyk A, Tikellis C, Thomas MC, Cooper ME, El-Osta A (2012) Distinguishing hyperglycemic changes by Set7 in vascular endothelial cells. Circ Res 110(8):1067–1076. https://doi.org/10.1161/CIRCRESAHA.112.266171

    Article  CAS  PubMed  Google Scholar 

  35. Miao F, Gonzalo IG, Lanting L, Natarajan R (2004) In vivo chromatin remodeling events leading to inflammatory gene transcription under diabetic conditions. J Biol Chem 279(17):18091–18097. https://doi.org/10.1074/jbc.M311786200

    Article  CAS  PubMed  Google Scholar 

  36. El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL, Roeder RG, Cooper ME, Brownlee M (2008) Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med 205(10):2409–2417. https://doi.org/10.1084/jem.20081188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Paneni F, Costantino S, Battista R, Castello L, Capretti G, Chiandotto S, Scavone G, Villano A, Pitocco D, Lanza G, Volpe M, Luscher TF, Cosentino F (2015) Adverse epigenetic signatures by histone methyltransferase Set7 contribute to vascular dysfunction in patients with type 2 diabetes mellitus. Circ Cardiovasc Genet 8(1):150–158. https://doi.org/10.1161/CIRCGENETICS.114.000671

    Article  CAS  PubMed  Google Scholar 

  38. Miao F, Wu X, Zhang L, Yuan YC, Riggs AD, Natarajan R (2007) Genome-wide analysis of histone lysine methylation variations caused by diabetic conditions in human monocytes. J Biol Chem 282(18):13854–13863. https://doi.org/10.1074/jbc.M609446200

    Article  CAS  PubMed  Google Scholar 

  39. Barsyte-Lovejoy D, Li F, Oudhoff MJ, Tatlock JH, Dong A, Zeng H, Wu H, Freeman SA, Schapira M, Senisterra GA, Kuznetsova E, Marcellus R, Allali-Hassani A, Kennedy S, Lambert JP, Couzens AL, Aman A, Gingras AC, Al-Awar R, Fish PV, Gerstenberger BS, Roberts L, Benn CL, Grimley RL, Braam MJ, Rossi FM, Sudol M, Brown PJ, Bunnage ME, Owen DR, Zaph C, Vedadi M, Arrowsmith CH (2014) (R)-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells. Proc Natl Acad Sci USA 111(35):12853–12858. https://doi.org/10.1073/pnas.1407358111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Costantino S, Paneni F, Luscher TF, Cosentino F (2016) MicroRNA profiling unveils hyperglycaemic memory in the diabetic heart. Eur Heart J 37(6):572–576. https://doi.org/10.1093/eurheartj/ehv599

    Article  CAS  PubMed  Google Scholar 

  41. Costantino S, Paneni F, Mitchell K, Mohammed SA, Hussain S, Gkolfos C, Berrino L, Volpe M, Schwarzwald CC, Lüscher TF, Cosentino F (2018) Hyperglycaemia-induced epigenetic changes drive persistent cardiac dysfunction via the adaptor p66Shc. Int J Cardiol. https://doi.org/10.1016/j.ijcard.2018.04.082

    Article  PubMed  Google Scholar 

  42. Zhong X, Liao Y, Chen L, Liu G, Feng Y, Zeng T, Zhang J (2015) The microRNAs in the pathogenesis of metabolic memory. Endocrinology 156(9):3157–3168. https://doi.org/10.1210/en.2015-1063

    Article  CAS  PubMed  Google Scholar 

  43. Zhao S, Li T, Li J, Lu Q, Han C, Wang N, Qiu Q, Cao H, Xu X, Chen H, Zheng Z (2016) miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway. Diabetologia 59(3):644–654. https://doi.org/10.1007/s00125-015-3832-0

    Article  CAS  PubMed  Google Scholar 

  44. Santovito D, De Nardis V, Marcantonio P, Mandolini C, Paganelli C, Vitale E, Buttitta F, Bucci M, Mezzetti A, Consoli A, Cipollone F (2014) Plasma exosome microRNA profiling unravels a new potential modulator of adiponectin pathway in diabetes: effect of glycemic control. J Clin Endocrinol Metab 99(9):E1681–E1685. https://doi.org/10.1210/jc.2013-3843

    Article  CAS  PubMed  Google Scholar 

  45. Paneni F, Costantino S, Cosentino F (2015) Molecular pathways of arterial aging. Clin Sci 128(2):69–79. https://doi.org/10.1042/CS20140302

    Article  CAS  Google Scholar 

  46. Aslibekyan S, Claas SA, Arnett DK (2015) Clinical applications of epigenetics in cardiovascular disease: the long road ahead. Transl Res 165(1):143–153. https://doi.org/10.1016/j.trsl.2014.04.004

    Article  CAS  PubMed  Google Scholar 

  47. Ordovas JM, Smith CE (2010) Epigenetics and cardiovascular disease. Nat Rev Cardiol 7(9):510–519. https://doi.org/10.1038/nrcardio.2010.104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gilbert RE, Huang Q, Thai K, Advani SL, Lee K, Yuen DA, Connelly KA, Advani A (2011) Histone deacetylase inhibition attenuates diabetes-associated kidney growth: potential role for epigenetic modification of the epidermal growth factor receptor. Kidney Int 79(12):1312–1321. https://doi.org/10.1038/ki.2011.39

    Article  CAS  PubMed  Google Scholar 

  49. Advani A, Huang Q, Thai K, Advani SL, White KE, Kelly DJ, Yuen DA, Connelly KA, Marsden PA, Gilbert RE (2011) Long-term administration of the histone deacetylase inhibitor vorinostat attenuates renal injury in experimental diabetes through an endothelial nitric oxide synthase-dependent mechanism. Am J Pathol 178(5):2205–2214. https://doi.org/10.1016/j.ajpath.2011.01.044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Xie M, Kong Y, Tan W, May H, Battiprolu PK, Pedrozo Z, Wang ZV, Morales C, Luo X, Cho G, Jiang N, Jessen ME, Warner JJ, Lavandero S, Gillette TG, Turer AT, Hill JA (2014) Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy. Circulation 129(10):1139–1151. https://doi.org/10.1161/CIRCULATIONAHA.113.002416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Beaudeux JL, Nivet-Antoine V, Giral P (2010) Resveratrol: a relevant pharmacological approach for the treatment of metabolic syndrome? Curr Opin Clin Nutr Metab Care 13(6):729–736. https://doi.org/10.1097/MCO.0b013e32833ef291

    Article  CAS  PubMed  Google Scholar 

  52. Waterland RA (2006) Assessing the effects of high methionine intake on DNA methylation. J Nutr 136(6 Suppl):1706S–1710S. https://doi.org/10.1093/jn/136.6.1706S

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

F.P. is the recipient of a Sheikh Khalifa’s Foundation Assistant Professorship at the Faculty of Medicine, University of Zürich. The present work is supported by the Zürich Heart House, the Swiss Heart Foundation, Swiss Life Foundation, the EMDO Stiftung; Kurt und Senta-Hermann Stiftung, and the Schweizerische Diabetes-Stiftung to F.P; the Holcim Foundation and the Swiss Heart Foundation (to S.C).

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  1. Division of Cardiovascular Epigenetics, Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, Schlieren, 8952, Zurich, Switzerland

    S. Costantino & F. Paneni

  2. University Heart Center, Cardiology, University Hospital Zurich, Zurich, Switzerland

    S. Ambrosini & F. Paneni

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Costantino, S., Ambrosini, S. & Paneni, F. The epigenetic landscape in the cardiovascular complications of diabetes. J Endocrinol Invest 42, 505–511 (2019). https://doi.org/10.1007/s40618-018-0956-3

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