Primary Prevention of Atherosclerosis
2012; Lippincott Williams & Wilkins; Volume: 125; Issue: 19 Linguagem: Inglês
10.1161/circulationaha.111.085787
ISSN1524-4539
AutoresClaudio Napoli, Valeria Crudele, Andrea Soricelli, Mohammed Al‐Omran, Nicoletta Vitale, Teresa Infante, Francesco Paolo Mancini,
Tópico(s)Congenital heart defects research
ResumoHomeCirculationVol. 125, No. 19Primary Prevention of Atherosclerosis Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBPrimary Prevention of AtherosclerosisA Clinical Challenge for the Reversal of Epigenetic Mechanisms? Claudio Napoli, MD, PhD, MBEth, Valeria Crudele, BiolD, Andrea Soricelli, MD, Mohammed Al-Omran, MD, Nicoletta Vitale, PhD, Teresa Infante, BiolD and Francesco P. Mancini, MD, PhD Claudio NapoliClaudio Napoli From the Department of General Pathology, Excellence Research Centre on Cardiovascular Diseases, U.O.C. Immunohematology, Transfusion Medicine and Transplant Immunology, Regional Reference Laboratory of Transplant Immunology, Azienda Universitaria Policlinico, 1st School of Medicine, Second University of Naples, Naples, Italy (C.N., V.C.); Fondazione SDN, Istituto di Ricovero e Cura a Carattere Scientifico, Naples, Italy (C.N., A.S., T.I.); Parthenope University, Naples, Italy (A.S.); Peripheral Vascular Disease Research Chair, College of Medicine, King Saud University, Riyadh, Saudi Arabia (M.A.-O.); and Department of Sciences for Biology, Geology, and Environment, University of Sannio, Benevento, Italy (N.V., F.P.M.). , Valeria CrudeleValeria Crudele From the Department of General Pathology, Excellence Research Centre on Cardiovascular Diseases, U.O.C. Immunohematology, Transfusion Medicine and Transplant Immunology, Regional Reference Laboratory of Transplant Immunology, Azienda Universitaria Policlinico, 1st School of Medicine, Second University of Naples, Naples, Italy (C.N., V.C.); Fondazione SDN, Istituto di Ricovero e Cura a Carattere Scientifico, Naples, Italy (C.N., A.S., T.I.); Parthenope University, Naples, Italy (A.S.); Peripheral Vascular Disease Research Chair, College of Medicine, King Saud University, Riyadh, Saudi Arabia (M.A.-O.); and Department of Sciences for Biology, Geology, and Environment, University of Sannio, Benevento, Italy (N.V., F.P.M.). , Andrea SoricelliAndrea Soricelli From the Department of General Pathology, Excellence Research Centre on Cardiovascular Diseases, U.O.C. Immunohematology, Transfusion Medicine and Transplant Immunology, Regional Reference Laboratory of Transplant Immunology, Azienda Universitaria Policlinico, 1st School of Medicine, Second University of Naples, Naples, Italy (C.N., V.C.); Fondazione SDN, Istituto di Ricovero e Cura a Carattere Scientifico, Naples, Italy (C.N., A.S., T.I.); Parthenope University, Naples, Italy (A.S.); Peripheral Vascular Disease Research Chair, College of Medicine, King Saud University, Riyadh, Saudi Arabia (M.A.-O.); and Department of Sciences for Biology, Geology, and Environment, University of Sannio, Benevento, Italy (N.V., F.P.M.). , Mohammed Al-OmranMohammed Al-Omran From the Department of General Pathology, Excellence Research Centre on Cardiovascular Diseases, U.O.C. Immunohematology, Transfusion Medicine and Transplant Immunology, Regional Reference Laboratory of Transplant Immunology, Azienda Universitaria Policlinico, 1st School of Medicine, Second University of Naples, Naples, Italy (C.N., V.C.); Fondazione SDN, Istituto di Ricovero e Cura a Carattere Scientifico, Naples, Italy (C.N., A.S., T.I.); Parthenope University, Naples, Italy (A.S.); Peripheral Vascular Disease Research Chair, College of Medicine, King Saud University, Riyadh, Saudi Arabia (M.A.-O.); and Department of Sciences for Biology, Geology, and Environment, University of Sannio, Benevento, Italy (N.V., F.P.M.). , Nicoletta VitaleNicoletta Vitale From the Department of General Pathology, Excellence Research Centre on Cardiovascular Diseases, U.O.C. Immunohematology, Transfusion Medicine and Transplant Immunology, Regional Reference Laboratory of Transplant Immunology, Azienda Universitaria Policlinico, 1st School of Medicine, Second University of Naples, Naples, Italy (C.N., V.C.); Fondazione SDN, Istituto di Ricovero e Cura a Carattere Scientifico, Naples, Italy (C.N., A.S., T.I.); Parthenope University, Naples, Italy (A.S.); Peripheral Vascular Disease Research Chair, College of Medicine, King Saud University, Riyadh, Saudi Arabia (M.A.-O.); and Department of Sciences for Biology, Geology, and Environment, University of Sannio, Benevento, Italy (N.V., F.P.M.). , Teresa InfanteTeresa Infante From the Department of General Pathology, Excellence Research Centre on Cardiovascular Diseases, U.O.C. Immunohematology, Transfusion Medicine and Transplant Immunology, Regional Reference Laboratory of Transplant Immunology, Azienda Universitaria Policlinico, 1st School of Medicine, Second University of Naples, Naples, Italy (C.N., V.C.); Fondazione SDN, Istituto di Ricovero e Cura a Carattere Scientifico, Naples, Italy (C.N., A.S., T.I.); Parthenope University, Naples, Italy (A.S.); Peripheral Vascular Disease Research Chair, College of Medicine, King Saud University, Riyadh, Saudi Arabia (M.A.-O.); and Department of Sciences for Biology, Geology, and Environment, University of Sannio, Benevento, Italy (N.V., F.P.M.). and Francesco P. ManciniFrancesco P. Mancini From the Department of General Pathology, Excellence Research Centre on Cardiovascular Diseases, U.O.C. Immunohematology, Transfusion Medicine and Transplant Immunology, Regional Reference Laboratory of Transplant Immunology, Azienda Universitaria Policlinico, 1st School of Medicine, Second University of Naples, Naples, Italy (C.N., V.C.); Fondazione SDN, Istituto di Ricovero e Cura a Carattere Scientifico, Naples, Italy (C.N., A.S., T.I.); Parthenope University, Naples, Italy (A.S.); Peripheral Vascular Disease Research Chair, College of Medicine, King Saud University, Riyadh, Saudi Arabia (M.A.-O.); and Department of Sciences for Biology, Geology, and Environment, University of Sannio, Benevento, Italy (N.V., F.P.M.). Originally published15 May 2012https://doi.org/10.1161/CIRCULATIONAHA.111.085787Circulation. 2012;125:2363–2373Innovative advances in understanding the pathogenesis of atherosclerosis have been achieved over the past 25 years. Although elevated levels of serum low-density lipoprotein cholesterol (LDL-C) are the major cause of onset of the disease, as established by a large number of superb epidemiological, clinical, and experimental studies, important novel factors have entered the arena of the atherogenic process. Besides the historical oxidative hypothesis that states that oxidized LDL, by escaping the homeostatic mechanism, strongly accelerates plaque formation, more recent evidence has given credit to vascular inflammation and apoptosis as crucial players in the progression of atherosclerosis.1–3 The disease has also been linked to the subintimal infiltration of immune cells and endothelial dysfunction induced by cardiovascular risk factors. Currently, endothelial dysfunction is considered one of the first stages of vascular damage and an early event in atherogenesis.1–3 Etiologic and pathogenetic factors, of both genetic and environmental origin, act together to promote local and systemic effects that lead to the onset, progression, and final outcome of the atherosclerotic disease. The clinical sequelae of atherosclerosis, myocardial infarction, stroke, and peripheral arterial disease depend on the affected vascular district, which in turn depends on complex gene-environment interplay.Despite the sudden occurrence of clinical symptoms, however, the evolution of atherosclerosis is very slow, which provides an opportunity for early diagnosis. In fact, a breakthrough in the field has been to recognize that although atherosclerosis generates severe diseases that most frequently affect middle-aged to old people, atherogenesis begins very early in life, even at the fetal stage.4,5 Primary prevention of any disease is more effective if started sooner. Therefore, it is of paramount importance to identify high-risk individuals and to initiate primary prevention in a timely manner, especially for atherosclerosis, which can begin its slow but relentless damage of the arterial wall even before birth. Epigenetic mechanisms have been recognized recently as possible modifiers of the risk of developing premature atherosclerosis. Therefore, the recognition of epigenetic markers that reveal a tendency to vascular diseases could be an effective aid in the early detection of at-risk individuals. These people can then be targeted for both lifestyle changes and pharmacological treatments to prevent or delay atherosclerotic disease. Although the pharmaceutical industry has provided invaluable preventive and therapeutic tools, general rules of best practice dictate that life habits be modified first, and only if intermediate markers of the disease do not normalize should at-risk individuals be given drug therapy. This approach also allows reducing the health care expenditure on the primary prevention of atherosclerosis-related disease.Early Onset of Human AtherogenesisThe prodromal stages of human atherosclerotic lesions are already set during fetal development.6–8 A seminal observation was that maternal hypercholesterolemia is associated with increased formation of fatty streaks in fetal arteries, which suggests that hypercholesterolemia is atherogenic even before birth.9Fetal lesions occur in the same arterial districts as those of adolescents and adults and are histologically similar to lesions that occur later in life.10 Moreover, there is evidence that fetal lesions can partially regress during the final stages of pregnancy or early infancy, when cholesterol levels are low.8 Atherosclerosis is significantly accelerated in children of mothers with high serum cholesterol compared with children of mothers with normal serum cholesterol. The mechanism by which maternal hypercholesterolemia can promote development of lesions in offspring has been explored in animal models.11–13 Indeed, lesions doubled in a litter of hypercholesterolemic mother rabbits compared with normocholesterolemic mother rabbits, and there was a linear correlation between maternal cholesterol and vascular injuries at birth.11 Consistently, a similar correlation was observed in LDL receptor–deficient mice.13 Maternal cholesterol levels increase physiologically from the first trimester and throughout the pregnancy, even in mothers with normal serum cholesterol levels14; this increase is much greater in mothers who are already hypercholesterolemic before pregnancy. Microarray analysis of aortas has shown that many genes are elevated or inhibited in the offspring of hypercholesterolemic mothers.15Children and young adults are also vulnerable to the effects of cardiovascular risk factors and show early signs of atherosclerosis, which becomes a complex process driven by conventional risk factors.16 Among cardiovascular risk factors, body mass index, systolic and diastolic blood pressure, serum total cholesterol, triglycerides, LDL-C, and high-density lipoprotein cholesterol are strongly associated with the extension of lesions in the aorta and coronary arteries. In addition, the severity of aortic and coronary artery disease in young people increases in proportion to the number of cardiovascular risk factors they face.6Epigenetic MechanismsEpigenetics deals with the mitotically and/or meiotically heritable variations of gene function that cannot be explained by changes of DNA sequence.17 The major consequence of epigenetic modifications is related to the packaging, and therefore the function, of the genetic material.18 Epigenetic modulation of gene expression is a central mechanism in development and differentiation of higher eukaryotes. The inherited cellular epigenetic setup directs the development of >250 cell types in humans; indeed, although the sequence of the DNA of the different cell types is identical within a single individual, the epigenetic modifications are quite different in the genomes of the different cells.The most frequent epigenetic modifications in mammals include DNA methylation and histone modifications, which result in changes in chromatin structure (Figure), and RNA-based alterations that involve microRNAs (miRNAs) and long intergenic noncoding RNAs (lincRNAs).19–21 Epigenetic mechanisms alter the accessibility of chromatin (a protein-DNA complex that consists of DNA, histones, and nonhistone proteins) by modifying DNA and nucleosomes, including posttranslational modifications of histones after interaction with environmental factors.22,23 Altered chromatin accessibility implies an increased or decreased possibility of interaction between gene regulatory regions and the transcription machinery, thus leading to variations of gene expression (Figure). In epigenetic processes, DNA methylation is generally associated with lower gene activity and is localized at the C5 position of cytosine residues in a CpG dinucleotide as a result of the action of DNA methyltransferases, which are capable of both methylation and demethylation, thus rendering the modification reversible.24,25 In vertebrates, CpG dinucleotides are concentrated in short interspersed DNA sequences that are called CpG islands. CpG islands are more often nonmethylated and favor a transcriptionally permissive chromatin state; however, they can undergo intense CpG methylation, thus silencing expression of surrounding genes.26,27 Moreover, posttranslational modifications of the N-terminal tails of histone proteins are pivotal events during the epigenetic regulation of genes.Download figureDownload PowerPointFigure. A, The maternal/fetal cholesterol hypothesis and epigenetics. Epigenetic modifications can accumulate throughout life, both prenatally and postnatally. In particular, during fetal life, maternal hypercholesterolemia can increase the risk of cardiovascular disease (CVD) in adult life in a dual fashion: It can promote initial arterial lesions, and it can induce proatherogenic epigenetic modifications. According to this view, cardiovascular risk factors can exert their negative influence from the beginning of life. The central role of statins in protection against CVD is recalled. B, Epigenetic modifications of DNA, namely, the addition of methyl groups to the cytosine of CpG islands, make chromatin more condensed and prevent access of the transcription preinitiation complex to regulatory regions, thus inhibiting gene expression. At the same time, histones are deacetylated by histone deacetylase and also contribute to switch off the genes. C, When DNA is not methylated but core histones are acetylated on specific lysine residues, chromatin is less condensed and transcriptionally active because the transcription preinitiation complex can bind to promoter regions and transcribe downstream genes. TBP indicates TATA binding protein; TFIIA, transcription factor IIA; TFIIB, transcription factor IIB; TFIID, transcription factor IID; RNA pol II, RNA polymerase II; TF, specific transcription factor; COR, corepressor; HDAC, histone deacetylase; COA, coactivator; and HAT, histone acetylase.To date, many modifications have been identified, including acetylation and methylation of lysine residues.20 Acetylation/deacetylation of lysines is correlated with chromatin accessibility and gene activation, whereas the role of histone methylation depends on the precise methylated residue and the number of added methyl groups.16,17 In addition, trimethylation of histones H3K9 and H3K27 might occur in inactive genes, whereas trimethylation of histones H3K4 and acetylation of H3/H4 are connected to active transcription.16 This chromatin plasticity is essential to maintain DNA in an open, permissive state. Thus, high levels of acetylation, together with trimethylation of H3K4, H3K36, and H3K79, have been found in transcribed genes; conversely, low levels of such modifications have been associated with inactive genes.16,21 Modifications of histones and DNA methylation are functionally linked activities. Throughout semiconservative DNA replication, the methylation of the daughter strand and recruitment of histone-modifying proteins retain the epigenome configuration in the next cell generation.28 Epigenetic modifications are naturally reversible, mainly because of the counterbalancing actions of the enzymes taking part in the maintenance of epigenome.29,30 The action of these enzymes restores a repressive or active chromatin state depending on specific sites. Therefore, these epigenetic events link mechanisms for genetic information integrity and epigenetic reprogramming. Other epigenetic mechanisms may involve acetyltransferases/deacetylases and methyltransferases/demethylases that also target nonhistone proteins, such as nuclear factor-κB.16 Further histone modifications other than lysine methylation and acetylation are known, such as the specific methylation and acetylation of arginine residues and the sumoylation and ubiquitination of histones31; however, the function of these modifications remains unclear.Epigenetics-Environment InteractionA major concept pertaining to epigenetics is its sensitivity to environmental stimuli. Interestingly, many of the environmental factors that are known to influence cardiovascular risk have been shown to also be associated with epigenetic modifications. Among others, nutrition can markedly affect epigenetic status, and this influence can also occur before birth and hence refer to the conditioning of the fetus by maternal nutrition. Important information came from studies on DNA methylation conducted in individuals exposed in utero to the Dutch Hunger Winter (Dutch famine of 1944–1945).32 Those people, in fact, were found to have significantly different methylation of several genes involved in metabolic regulation compared with control subjects.33 Most interestingly, people with the same gestational exposure were at increased sex-specific risk of hyperlipidemia, obesity, and mortality from myocardial infarction and ischemic stroke during adult life compared with control subjects who were not exposed prenatally to famine.34 Consistently, low birth weight was associated with increased incidence of coronary artery disease later in life.35In addition, experimental data support the thesis that maternal diet can profoundly affect the epigenetic status of the fetal genome and that maternally induced epigenetic modifications are maintained throughout adulthood.36 In some cases, altered histone methylation and expression of lysine methyltransferase were observed in atherosclerotic tissues, thus suggesting a direct involvement of chromatin structure in the atherogenic process.37 Additional data demonstrated that prenatal protein restriction was associated with altered DNA methylation of genes involved in lipid metabolism.38 In addition, zinc deficiency has been associated with cardiovascular disease (CVD), and dietary zinc restriction in rats during fetal life, lactation, and the postweaning stage causes hypertension and renal impairment in adult life.39Similar to maternal diet, maternal tobacco smoking induces epigenetic changes in the fetal genome. Several loci were hypomethylated in children exposed to maternal smoking during gestation compared with controls, and the same children developed increased risk of diseases later in life.40,41Finally, environmentally induced epigenetic modifications do not take place exclusively during prenatal life but can occur at any age, including during adult life.42 For example, 2 conditions that introduce contaminated air into the lungs, cigarette smoking and exposure to pollution from traffic, have been associated with modification of DNA methylation in exposed individuals.43,44Epigenetics and AtherosclerosisIn light of the accumulating evidence, epigenetic mechanisms have been recognized as important mediators of the atherogenic process at its earliest stages and of consequent CVD. Alterations of epigenetic programming are not limited to CVD but have been implicated in several common human diseases and conditions, such as cancer, diabetes, neurological disorders, imprinting disorders, autoimmune diseases, and aging. Fetal exposure to maternal hypercholesterolemia has been associated with increased risk and progression of atherosclerosis both in humans and in experimental models, and hypomethylation of DNA is a landmark of advanced atherosclerotic lesions in humans and laboratory animals.8,45 Moreover, it has been shown that global hypomethylation of DNA extracted from human aortic lesions is caused in part by the near-complete demethylation of the subset of CpG islands that are hypermethylated in control aortas.46 In contrast, globally hypermethylated DNA from peripheral blood leukocytes was associated with the prevalence of CVD as well as specific hypermethylation, and decreased expression of the tissue factor pathway inhibitor 2 gene was detected in atherosclerotic plaques.46,47In addition to methylation of large genomic regions, more specific epigenetic modifications can provide an essential contribution to the development of atherosclerosis. A sound hypothesis states that hypomethylation of atherosclerosis-susceptibility genes and hypermethylation of atherosclerosis-resistance genes cause overexpression and underexpression of these genes, respectively, thus favoring plaque formation. Among others, the DNA methylation of antiproliferative genes, such as that coding for estrogen receptor-α, was demonstrated in human atherosclerotic plaques, which suggests that this mechanism could be responsible for the proliferative events of atherogenesis, especially with reference to smooth muscle cells.48 As is always the case, a simple association between 2 events does not distinguish the cause from the consequence. For example, a CpG island of extracellular superoxide dismutase, which is overexpressed in experimental atherosclerosis, was reported to be hypomethylated in atherosclerotic lesions of rabbits.49,50 In contrast with the previous example, this epigenetic modification could be the nuclear response strategy of the diseased tissue to fight the progression of atherosclerosis.Epigenetics also plays an important role in controlling inflammatory processes that are activated within the vascular wall by atherogenic stimuli and, in a vicious circle, aggravate the atherosclerotic degeneration of the involved arteries.51 Epigenetic mechanisms can also affect CVD by influencing the expression of atherosclerosis-related genes via modulation of transcription factors. These proteins can be divided into 4 classes (I through IV) classified by structural elements that mediate their DNA binding activity but also determine the classes of drugs that can affect their activity.20,52 It is known that statins modulate the activation of sterol responsive element-binding protein, a class I transcription factor whose target genes are involved in cholesterol and fatty acid metabolism.53 Similarly, insulin-like drugs target the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ, a class II transcription factor), and several anti-inflammatory drugs inhibit the activation of nuclear factor-κB (a class IV transcription factor), whereas others (eg, flavopiridol, rapamycin, and paclitaxel) regulate cell-cycle proteins.52 In addition, the Mediator complex (consisting of ≈30 subunits), which regulates transcription by RNA polymerase II, has been suggested to play a role in epigenetic mechanisms because it is involved in gene expression and chromatin architecture.54–57Alterations of lipid metabolism have been associated with aortic methylation patterns in hyperlipidemic mice, whereas it has been shown recently that the triglyceride-rich very low-density lipoprotein (VLDL) causes de novo DNA methylation in human cultured macrophages. A possible interface between lipid molecules, epigenetic modifications, and atherosclerosis is provided by PPARs (including the previously mentioned PPAR-γ), which are nuclear receptors that control lipid and glucose metabolism, as well as adipogenesis and some inflammatory pathways.58–60 In fact, PPARs bind lipid molecules and regulate transcription of target genes by recruiting coactivators and corepressors, typically histone acetyltransferases or histone deacetylases, respectively. Furthermore, PPAR activity is sensitive to resveratrol, a dietary polyphenol with antioxidant and atheroprotective potentials that also activates sirtuins, a class of NAD+-dependent deacetylases.61,62 Therefore, PPARs, and PPAR-γ in particular, are good candidates to be at the interface between nutritional stimuli and epigenetic modifications.Not only is there a vast knowledge base about specific genes involved in CVD, but more information is available concerning chromosomal loci that could be relevant for the onset and evolution of this disease. Recent genome-wide association studies have identified multiple loci that are associated with atherosclerotic phenotypes. Among these, the chromosomal 9p21 locus shows one of the strongest associations with CVD.63,64 The locus encompasses multiple single-nucleotide polymorphisms that are in strong linkage disequilibrium, forming a risky haplotype that is associated with a 20% to 30% increase in coronary artery disease risk. Variants in the chromosomal 9p21 region are associated with various pathological events, including stroke, abdominal aortic aneurysm, peripheral vascular disease, diabetes, and dementia, as well as with nonatherosclerotic phenotypes such as intracranial aneurysm, endometriosis, and cancers.63–66 The association of 9p21 variants with atherosclerosis has been confirmed in multiple white cohorts and populations of different ethnicities63; however, the mechanisms through which the 9p21 locus influences atherosclerosis susceptibility remain incompletely understood. The identification of entire genomic regions involved in CVD is particularly relevant to the study of epigenetic modification and CVD itself.More recently, it has been shown that noncoding RNAs influence epigenetic changes of DNA methylation and histone code in CVD.16 Many microRNAs have already been identified, and some of them are also involved in vascular inflammation and atherosclerosis.67–71 Of note, miR-33, an intronic microRNA, has been found to modulate the expression of genes involved in cellular cholesterol transport.72 The epigenetic mechanisms involved in CVD are described in Table 1.Table 1. Epigenetic-Regulated Genes Involved in Cardiovascular DiseaseGeneEpigenetic MechanismRisk Factor for CVDeNOSDNA methylation and histone modificationPersistent pulmonary hypertension of the newbornFads2DNA methylationHyperhomocysteinemiaERαDNA methylationAging and atherosclerosisERβDNA methylationAtherosclerosisP66ShcDNA methylationEnd-stage renal diseaseEC-SODDNA methylationAtherosclerosisH19/Igf2DNA methylationHyperhomocysteinemiaTIMP-3DNA methylationCardiac dysfunctionSREBF-2miRNACholesterol transportApoEDNA methylation and histone modificationHypercholesterolemia and atherosclerosisLDLRDNA methylation and histone modificationAtherosclerosisLXRDNA methylationPrenatal protein restriction/birth weightPPARsDNA methylationMetabolic syndromeGRDNA methylation and histone modificationProtein-restricted diet during pregnancyeNOS indicates endothelial nitric oxide synthase; Fads2, fatty acid desaturase 2; ER, estrogen receptor; EC-SOD, superoxide dismutase 3, extracellular; Igf2, insulin-like growth factor 2; TIMP-3, tissue inhibitor of metalloproteinase 3; SREBF-2, sterol regulatory element binding factor 2; ApoE, apolipoprotein E; LDLR, low-density lipoprotein receptor; LXR, liver X receptor; PPARs, peroxisome proliferator-activated receptors; and GR, glutathione reductase.Modified from Napoli et al.16Epigenetics and Therapeutic InsightsThe relatively reversible nature of epigenetic alterations has inspired the development of therapeutic strategies targeting various epigenetic components.16 Epigenetics-based therapies are being developed and represent a promising strategy for many diseases and areas of medicine. In regenerative medicine, it is possible to generate pluripotent cells from human somatic cells by modifying epigenetic profiles; however, there are several preliminary issues that need to be addressed before epigenetic therapies become a clinical routine. First, in atherosclerosis, as in other diseases, the physiological and pathological human epigenome must be elucidated. Second, once the genes or loci that are associated with the disease and are epigenetically altered are known, a therapeutic procedure that specifically targets those genes must be defined. Indeed, there is the risk of modifying gene expression in a nonspecific manner, thus generating undesirable side effects. However, DNA methyltransferase inhibitors and histone deacetylase inhibitors have been studied in clinical trials, and some of these agents have also been approved for treatment of malignancies.73Recently, histone methylation and microRNA expression have been considered as potential therapeutic targets for treating diseases.74 Regarding the connection between histone acetylation/deacetylation and atherosclerosis, there is ample evidence that histone acetyltransferases and histone deacetylases have a relevant role in inflammation, smooth muscle cell proliferation, and extracellular matrix remodeling, all processes that are central to atherogenesis.75 Indeed, epigenetic modifications of histones modulate the function of several factors, such as nuclear factor-κB, granulocyte macrophage–colony stimulating factor, eotaxin, cyclooxygenase 2, serum response factor, cell cycle regulators, and matrix metalloproteinase-1, -2, -3, -9, and -13.75 Moreover, administration of curcumin (a natural antioxidant, with several reported healthy effects and a histone acetyltransferase inhibiting activity) resulted in significantly lowered LDL lev
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