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Epigenetic Mechanisms in Diabetic Vascular Complications and Metabolic Memory: the 2020 Edwin Bierman Award Lecture

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Epigenetic Mechanisms in Diabetic Vascular Complications and Metabolic Memory: the 2020 Edwin Bierman Award Lecture 328 Diabetes Volume 70, February 2021 Epigenetic Mechanisms in Diabetic Vascular Complications and Metabolic Memory: The 2020 Edwin Bierman Award Lecture Rama Natarajan Diabetes 2021;70:328–337 | https://doi.org/10.2337/dbi20-0030 Macrovascular complications such as atherosclerosis, It was truly an honor to deliver the 2020 Edwin Bierman myocardial infarction and stroke, and microvascular com- Award Lecture at the 80th ScientificSessionsofthe plications such as nephropathy, retinopathy, and neurop- American Diabetes Association. I dedicate this award to athy are the major causes of increased morbidity and the victims of the COVID-19 pandemic and to our health mortality in both type 1 and type 2 diabetes. Increased care workers, heroes of these challenging times. It was inflammation, oxidative stress, and fibrosis are common a unique experience prerecording this talk all alone in my features in most diabetes complications. Although exten- office via a zoom portal and then watching it on June 13th sive studies have examined the biochemical pathways while responding to text messages from other attendees. fl fi leading to the expression of in ammatory, pro brotic, Our kudos to the organizers for bravely embarking on this and other pathological genes, as well as genetic factors very first virtual Scientific Sessions. related to diabetes and associated complications, much Dr. Edwin Bierman’s pioneering work in the fields of less is known about the contribution of epigenetic diabetes, obesity, and atherosclerosis has inspired so many changes that occur without alterations in the DNA se- scientists, including me, and emphasized the role of aber- quence. Environmental factors, lifestyles, and improper rant lipid metabolism in diabetic vascular disease. Chronic diet implicated in diabetes can affect epigenetic states. elevation in blood glucose levels in both type 1 diabetes ADA AWARD LECTURE Epigenetic modifications, including DNA methylation (T1D) and type 2 diabetes (T2D) can cause blood vessel and histone modifications, can alter gene transcription in damage. Damage to arteries increases macrovascular com- response to environmental stimuli and cooperate with noncoding RNAs. These epigenetic modifications have plications including cardiovascular diseases (CVDs) such as been observed in various target cells under diabetic atherosclerosis, myocardial infarction, hypertension, and conditions. Moreover, epigenetics has also been im- stroke, while damage to small blood vessels results in plicated in the phenomenon of metabolic memory ob- microvascular complications such as nephropathy, neu- served in clinic trials and animal studies, in which prior ropathy, and retinopathy. These complications lead to fi – episodes of poor glycemic control can confer continued signi cantly increased morbidity and mortality (1 4). risk of complications despite subsequent glucose Because of shared mechanisms leading to vessel damage, normalization. Epigenome-wide association studies in micro- and macrovascular complications frequently coex- cohorts with diabetes are uncovering epigenotype var- ist, with diabetic nephropathy (diabetic kidney disease iations that provide new insights into diabetic vascular [DKD]) being a major risk factor for CVDs (4). complications. Here, I discuss the role of epigenetics and Genetic disposition and key single nucleotide polymor- noncoding RNAs in diabetes complications and meta- phisms have been implicated in both T1D and T2D com- bolic memory, and their translation potential to serve as plications. However, increasing evidence suggests that biomarkers and drug targets to improve clinical man- complex interactions between genes and the environment agement of diabetic vascular complications. may also be involved (5–7). Notably, nuclear chromatin is Department of Diabetes and Metabolic Diseases Research, Diabetes Metabolic © 2021 by the American Diabetes Association. Readers may use this article as Research Institute, Beckman Research Institute of City of Hope, Duarte, CA long as the work is properly cited, the use is educational and not for profit, and the Corresponding author: Rama Natarajan, [email protected] work is not altered. More information is available at https://www.diabetesjournals .org/content/license. Received 9 August 2020 and accepted 16 October 2020 The 2020 Edwin Bierman Award Lecture was presented virtually at the American Diabetes Association’s 80th Scientific Sessions on 13 June 2020. diabetes.diabetesjournals.org Natarajan 329 a crucial interface between the effects of genetics and Hyperglycemia, a common feature of both T1D and T2D environment, and the epigenetic modifications in chroma- and a major risk factor for diabetes complications, es- tin including DNA methylation (DNAme) and posttran- pecially microvascular, can act via production of AGEs; scriptional modifications (PTMs) of histone tails, along oxidized lipids; inflammatory cytokines such as tumor with noncoding RNAs, regulate gene transcription. Al- necrosis factor-a (TNF-a), interleukin-1b and interleukin- though several studies have identified key biochemical 6; growth factors such as angiotensin II (AngII); and pathways triggered by hyperglycemia and diabetes in transforming growth factor-b1 (TGF-b1) in target cells target cells leading to expression of genes related to di- (4,7,9,13). Several signal transduction pathways down- abetes complications, the role of epigenetic mechanisms is stream of HG, AGEs, dyslipidemia, and growth factors becoming increasingly evident. Clinical trials have empha- activate various kinases and TFs such as NF-kB, CREB, and sized the benefits of intensive glycemic control for re- SMADs. These TFs regulate the expression of inflamma- ducing the risk of progression of complications. Even tory cytokines and growth factors as well as fibrotic and though diabetes can be controlled through medications, growth-related genes associated with CVDs and other insulin, and lifestyle modifications, in some subjects with diabetes complications (3,4,7). These processes regulate diabetes, prior periods of hyperglycemia due to relaxed coding genes as well as noncoding genes such as miRNAs glycemic control can be associated with continued risk of and long noncoding RNAs (lncRNAs) that modulate di- complications long after hemoglobin A1c (HbA1c) levels abetes complications (7). Moreover, diabetes also disrupts have been normalized. This “metabolic memory” of prior key endogenous protective processes such as antioxidant glycemic control could be due to epigenetic changes in factors, autophagy, and mitophagy (3). target cells. In the Edwin Bierman Award Lecture, I out- Our laboratory began investigating potential epigenetic lined contributions from our laboratory and others to our mechanisms (defined in the next section) in the regulation understanding of epigenetics and epigenomics related to of genes and processes associated with diabetic vascular diabetic vascular complications and metabolic memory and complications and metabolic memory. This is because potential implications for much-needed new therapies. gene-environment interactions, viruses, improper diet, and sedentary lifestyles, all of which affect epigenetics, Vascular Complications of Diabetes: Inflammation and augment risk for diabetes, inflammation, and related Fibrosis Are Key Culprits complications (7,13). Key events in macrovascular complications such as ath- erosclerotic plaque formation include activation of mono- Epigenetics and Epigenomics: New Insights Into cytes and endothelial cells (ECs); transendothelial migration Complications of monocytes and their differentiation into macrophages, Epigenetics is broadly defined as mitotically and/or mei- which become lipid-laden foam cells; and proliferation and otically heritable changes in gene expression and function migration of vascular smooth muscle cells (VSMCs) (2). that occur without changes in the underlying DNA se- Several experimental models in animals have illustrated quence (14,15). Epigenetic changes can occur dynamically mechanisms associated with diabetes-induced accelerated in response to developmental, environmental, and nutri- CVDs (4,8,9). In early collaborations with Gerrity and tional cues to regulate gene expression, phenotypes, and colleagues (10), we observed markedly increased oxidative metabolic abnormalities, some of which are heritable. stress in monocytes obtained from a swine model of Epigenetic changes can lead to discordant phenotypes and diabetes-induced accelerated atherosclerosis. In addition, disease susceptibility among genetically identical twins we found that treatment of VSMCs and human monocytes (5–7). with high glucose (HG) (15–25 mmol/L) or advanced Nuclear chromosomal DNA is tightly packaged with glycation end products (AGEs) mimicking the diabetes histone proteins into chromatin, which consists of sub- state leads to the activation of NF-kB and AP-1 transcrip- units called nucleosomes. Each nucleosome is composed of tion factors (TFs) associated with the transcriptional reg- an octameric histone protein complex containing dimers of ulation of inflammatory genes like cytokines and adhesion core histones H2A, H2B, H3, and H4 and wrapped with molecules (11,12). These and several subsequent studies 147 base pairs of DNA. Apart from the binding of TFs have clearly highlighted inflammation as a major feature of to promoters and classic transcription mechanisms, gene diabetic vascular disease, causing accelerated dysfunction regulation can also be affected by epigenetic changes of vascular and inflammatory
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