Green and Brewer Clinical Epigenetics (2020) 12:59 https://doi.org/10.1186/s13148-020-00848-y REVIEW Open Access Dysregulation of 2-oxoglutarate-dependent dioxygenases by hyperglycaemia: does this link diabetes and vascular disease? Hannah L. H. Green and Alison C. Brewer* Abstract The clinical, social and economic burden of cardiovascular disease (CVD) associated with diabetes underscores an urgency for understanding the disease aetiology. Evidence suggests that the hyperglycaemia associated with diabetes is, of itself, causal in the development of endothelial dysfunction (ED) which is recognised to be the critical determinant in the development of CVD. It is further recognised that epigenetic modifications associated with changes in gene expression are causal in both the initiation of ED and the progression to CVD. Understanding whether and how hyperglycaemia induces epigenetic modifications therefore seems crucial in the development of preventative treatments. A mechanistic link between energy metabolism and epigenetic regulation is increasingly becoming explored as key energy metabolites typically serve as substrates or co-factors for epigenetic modifying enzymes. Intriguing examples are the ten-eleven translocation and Jumonji C proteins which facilitate the demethylation of DNA and histones respectively. These are members of the 2-oxoglutarate-dependent dioxygenase superfamily which require the tricarboxylic acid metabolite, α-ketoglutarate and molecular oxygen (O2) as substrates and Fe (II) as a co-factor. An understanding of precisely how the biochemical effects of high glucose exposure impact upon cellular metabolism, O2 availability and cellular redox in endothelial cells (ECs) may therefore elucidate (in part) the mechanistic link between hyperglycaemia and epigenetic modifications causal in ED and CVD. It would also provide significant proof of concept that dysregulation of the epigenetic landscape may be causal rather than consequential in the development of pathology. Keywords: Diabetes, Hyperglycaemia, 2-oxoglutarate-dependent dioxygenase, TET proteins, JmjC proteins, Oxygen, Cellular redox, Metabolism, DNA methylation, Histone methylation Introduction most common cause of mortality in affected individuals A startling increase in obesity driven by a sedentary life- [3]. Further, the phenomena of hyperglycaemic memory, style and high-calorie diet has resulted in a worldwide where phenotypic alterations persist despite the restor- epidemic of type 2 diabetes (T2D) that is set to further ation of normal glycaemic control, renders CVD a life- rise dramatically [1, 2]. Thus, current estimates suggest long risk to individuals who have been affected by that by 2045, 700 million people will be living with dia- diabetes. This predisposition to CVD additionally affects betes [2]. The hyperglycaemia characteristic of diabetes the offspring of mothers who exhibit gestational diabetes represents a major risk factor for the development of (defined as glucose intolerance resulting in hypergly- cardiovascular disease (CVD) which is ultimately the caemia with onset or first discovery in pregnancy), cases of which have similarly burgeoned with the obesity crisis * Correspondence: [email protected] [4]. Such developmental priming has also been shown to School of Cardiovascular Medicine & Sciences, King’s College London British exhibit inheritance to the second (F2) generation and Heart Foundation Centre of Research Excellence, London, UK © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Green and Brewer Clinical Epigenetics (2020) 12:59 Page 2 of 15 therefore additionally compounds the current problems and polyol pathways leading to the production of ad- onto the future population [5, 6]. The economic burden vanced glycosylation end-products (AGEs) [28–30]. associated with this is vast and in the current economic However, these mechanisms cannot account for the ob- climate, unaffordable. It is therefore vital that better pre- servation of hyperglycaemic memory, including develop- ventative and therapeutic clinical strategies are devel- mental priming. It is now evident from epidemiological oped. The underlying mechanisms which predispose and clinical studies that the development of T2D and as- individuals who are, or have in the past been exposed to, sociated CVD is correlated with, and in part depends hyperglycaemia must therefore be determined. upon, environmentally influenced epigenetic changes which modulate gene expression (reviewed in [31]). The Hyperglycaemia, endothelial dysfunction and term epigenetics has come to mean heritable alterations cardiovascular disease in gene expression and phenotype that do not involve Diabetes is associated with the development of compli- changes in the primary DNA sequence [32]. Epigenetic cations affecting both the microvasculature (diabetic ret- mechanisms thus involve stable cellular modifications, inopathy, neuropathy and nephropathy) and capable of governing functional changes in gene expres- macrovasculature (peripheral artery disease, cardiomy- sion patterns in response to external environmental opathy, myocardial infarction and stroke) [7]. Macrovas- stimuli, or as part of normal development [33]. Epigen- cular complications are primarily responsible for the etic modifications include changes to histone post- reduced life expectancy of diabetic patients; T2D is asso- translational modifications, non-coding RNA and DNA ciated with a two to sixfold greater risk of cardiovascular methylation patterns, which serve to activate or repress mortality than amongst non-diabetics [8, 9] and similarly transcription of a gene [32]. In essence, epigenetic modi- high relative risks are reported for type 1 diabetics [10]. fications govern remodelling of chromatin, placing it in It is well established that the dysfunction of the vascular a conformation which is ‘open’ (euchromatin) or ‘closed’ endothelium, which comprises the one cell thick, inner- (heterochromatin) to transcription factors and other most layer of the vascular wall is both a hallmark of vas- transcription machinery [32]. The epigenetic landscape cular disease and is critical in the development of both of a cell is thus a major regulator of gene transcription macrovascular and microvascular pathologies [11, 12]. and accounts for the vastly different phenotypes and Endothelial dysfunction (ED) is characterised by a proin- functions of cells containing identical DNA, providing a flammatory, prothrombotic state with impaired vasodila- link between phenotype and genotype. tion [11, 13, 14] and a reduced bioavailability of the critical vascular mediator, nitric oxide (NO) [11]. Given Hyperglycaemia and epigenetic regulation the direct contact between endothelial cells (ECs) and Although not documented here, the (ever-increasing) blood, it is not surprising that they are critically affected recognised associations between changes in the epige- by metabolic changes in blood plasma such as hypergly- nome and T2D-related CVD are the subject of many ex- caemia. Indeed, a significant body of evidence from cellent reviews [34–37]. Further, the study of the in vitro studies suggests that hyperglycaemia per se is regulation of these epigenetic changes in the aetiology causative in the development of ED [15–27]. Thus, it has and progression of ED and CVD in diabetes is an emer- been shown that even short-term exposure of ECs to ging field. The influence of high glucose upon the EC high glucose is sufficient to induce monocyte adhesion epigenetic landscape and transcriptome has clearly been [15], promote endothelial to mesenchymal transition demonstrated in vitro. Thus in an important study, it [16], activate prothrombotic signalling [20], reduce was shown that the incubation of human aortic endothe- eNOS activity [21] and increase apoptosis [22]. High- lial cells (HAECs) in high glucose (30 mM) for 2 days re- glucose culture conditions also enhanced the response sulted in significant changes in the expression of genes of human umbilical vein endothelial cells (HUVECs) to associated with diabetes and vascular complications, the pro-inflammatory stimulus interleukin-1β, resulting many of which correlated with (histone and DNA) epi- in augmented endothelial ICAM-1 and VCAM-1 expres- genetic changes at these loci [38]. Thus, hyperglycaemia sion and promoting increased leukocyte adhesion [26], per se can mediate epigenetic changes that associate further demonstrating the effect of hyperglycaemia upon with changes in transcription