Atherosclerosis is the leading cause of mortality and morbidity in the developed world. It is characterized by the formation of a plaque in the walls of middle and large arteries leading to macrovascular complications. Several risk factors are included, with diabetes being one of the most important for the onset and development of atherosclerosis. Due to an increase in the prevalence of diabetes in the world, the incidence of diabetic complications (microvascular and macrovascular) is increasing. Peroxisome proliferator-activated receptor γ (PPARγ) plays a important role in atherosclerotic processes. Peroxisome proliferator activated receptor γ belongs to the superfamily of nuclear receptors, has a great presence in fat tissue, macrophages, and regulates gene expression and most of the processes that lead to the onset and development of atherosclerosis. In this review, we discuss the basic patho-physiological mechanisms of atherosclerosis in type 2 diabetes mellitus (T2DM). Furthermore, we discuss the impact of PPARγ polymorphisms, and the epigenetic mechanisms affecting the onset of atherosclerosis, i.e, DNA methylation and demethylation, histone acetylation and deacetylation, and RNA-based mechanisms. Moreover, we add therapeutic possibilities for acting on epigenetic mechanisms in order to prevent the onset and progression of atherosclerosis.
Atherosclerosis is a long-term process characterized by plaque formation in middle and large arterial blood vessels . Atherosclerosis is one of the leading causes of stroke, heart attack and peripheral arterial disease [2, 3]. The prevalence and degree of atherosclerosis increases with increasing age, body mass index (BMI), increased blood pressure (BP), and serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) . An elevated level of LDL is directly associated with development of atherosclerotic cardiovascular disease (ASCVD) . According to the National Hearth, Lung and Blood Institute (NHLBI) data, atherosclerosis begins when certain factors such as smoking, high cholesterol, high BP and high blood sugar levels due to insulin resistance or diabetes damage the inner layers of the arteries. Other factors that have a significant effect on the development of atherosclerosis include family history, older age, unhealthy diet, lack of physical activity . Depending on the position and size of the atherosclerotic plaque, microvascular and macrovascular complications of atherosclerosis can seriously damage the brain, heart, kidneys and other organs. Atherosclerotic disease of the carotid and coronary arteries appears to be highly prevalent in the ageing population .
Coronary atherosclerosis is the leading cause of coronary artery disease (CAD) . Three pathological processes affect the formation of plaque: inflammatory reaction, cell proliferation and differentiation of foam cells . The preliminary step in the formation of plaque is the passage of monocytes into subendothelial space and their differentiation into macrophages, which favor the oxidation of LDL particles in the blood and their endocytosis in the cells [8, 9]. Endocytosis is mediated by scavenger receptors, which are not inhibited by content of cell cholesterol, that results in the accumulation of lipids in macrophages and foam cells. Activated macrophages secrete inflammatory cytokines [macrophage-colony stimulating factor (M-CSF), tumor necrosis factor α (TNFα) and interleukin 1 (IL-1)] that trigger inflammatory processes and lead to proliferation of smooth muscle cells (SMCs). Then, macrophages and foam cells necrotize that leads to the release of the contents into the extracellular space, which is the basis for the onset of atherosclerosis . Peroxisome proliferator-activated receptors (PPARs) modulate many aspects of these processes [8, 9].
The aim of this review was to discuss the relationship between the peroxisome proliferator-activated receptor γ (PPARγ) gene polymorphisms and macrovascular complications of carotid and coronary arteries in patients with type 2 diabetes mellitus (T2DM). Moreover, we discussed epigenetic mechanisms affecting the onset of atherosclerosis and therapeutic possibilities affecting epigenetic mechanisms in order to prevent the onset and progression of atherosclerosis.
The PPARγ and Its Role in the Development of Atherosclerosis. Peroxisome proliferator-activated receptors are members of the steroid/thyroid hormone receptor superfamily of transcription factors that are encoded by three PPAR genes: PPARα, PPARβ/δ and PPARγ. The PPARγ gene has two isoforms of PPARγ1 and PPARγ2 that are ligand-activating transcription factors . The PPARγ gene is most prevalent in fatty tissue and macrophages and is very important in regulation of gene expression in metabolism and inflammation . The PPARγ transcriptional activity was modulated by binding of numerous fatty acid metabolites that activate PPARγ. Activated PPARγ increases the expression of the scavenger receptor, which transmits ox-LDL from blood to macrophages, which then differentiates into foam cells [11, 12]. By collecting foam cells, necrotic tissue residues, migrating and proliferating VSMCs (vascular smooth muscle cells), an atheromatous plaque is formed . Overweight patients, T2DM patients and non diabetic patients, have increased PPARγ (γ1 and γ2) values, associated with changes in BMI and fasting insulin. Deviations from PPARγ values indicate a possible role in the onset of insulin resistance of skeletal muscles in obesity and diabetes . Thus, PPARγ is involved in the regulation of all the steps that precede the onset of atheromatous plaque, therefore, the occurrence of mutations in PPARγ might be an initial step for the onset of atherosclerosis.
Polymorphisms of the PPARγ Gene, Genetic Biomarkers for Atherosclerosis. Several studies have shown an association between the PPARγ polymorphisms and microvascular and macrovascular complications of coronary and carotid arteries in patients with T2DM [13, 14, 15].
In a study with a relatively small number of subjects (161) and a relatively young average lifespan (38.0 ± 15.3), Al-Shali et al.  found a link between PPARγ genotypes and carotid atherosclerosis. They measured the thickness of carotid intima media (IMT) and total plaque volume (TPV), and found that subjects with the PPARG A12 allele had lower IMT (0.72 ± 0.03 mm; p = 0.0045), without differences in TPV, and subjects with the PPARG c.1431T allele have higher TPV (124.0 ± 18.4; p = 0.0079) without differences in IMT . According to Li et al. , the Pro12Ala polymorphism modulates PPARγ activity and leads to changes in the regulation of insulin sensitivity and glucose tolerance that ultimately leads to ASCVD [allelic model: odds ratio (OR) 0.80; 95% confidence interval (95% CI) 0.66-0.98, p = 0.040; dominant model: OR 0.74, 95% CI; 0.58-0.95, p = 0.033). In their meta-analysis, 12 case-control studies (eight Caucasian, three Asian and one African) were included with 10,189 cases with ASCVD [myocardial infarction (MI), CAD and acute coronary syndrome (ACS)] and 17,899 control subjects . Yan et al.  found that the CC genotype of the C16T polymorphism (rs3856806) was associated with carotid lesions, while the CT+TT genotype had a protective role, indicating the important role of the C161T polymorphism in carotid artery atherosclerosis. In the carotid artery of patients with metabolic syndrome, CC genotype vs. CT+TT genotype significantly increased IMT and plaque index (IMT: 0.84 ± 0.3 mm; plaque index: 2.19 ± 1.21; p <0.05) . In a study on Thai subjects, Yongsakulchai et al.  found that the combination of PPARγ polymorphisms rs3856806 (C1431T), rs8192678 (G482S) and liver X receptor-α (LXRα) polymorphism rs12221497 (115G/A) predict the development and progression of coronary atherosclerosis in subjects at-risk for CAD, and that the central role in this process belongs to rs8192678 polymorphism (OR 1.64, 95% CI: 1.01 ± 2.66, p: 0.048). In their study, 387 subjects were included, aged between 35-85 years, of whom 225 had CAD and 162 non CAD subjects (CAD group = stenosis ≥50.0% and non CAD group = stenosis ≤50.0%, at least one of the major coronary arteries) .
Few studies have shown that there was no statistically significant relationship between PPARγ polymorphisms and atherosclerosis[18, 19, 20]. Wang et al.  in a meta-analysis involving 29 studies (15 Caucasian, 13 Asian and one African), with PPARγ polymorphisms rs1801282 (Pro12Ala)/rs3856806 (C161T), did not find a statistically significant relationship with the onset of atherosclerotic diseases. In their meta-analysis, they analyzed different genetic models and associations with atherosclerotic disorders, there were no statistically significant results for the polymorphism rs1801282 .
However, for the polymorphism rs3856806, based on ethnicity, they found a significantly increased risk for ath-erosclerotic disease in Caucasians (2679 cases with atherosclerotic disease and 5121 control subjects) for the additive model (OR 1.72; 95% CI 1.12-2.66) and for the recessive model (OR 1.71; 95% CI 1.11-2.62), whereas the risk for the Asian population (1910 cases with atherosclerotic disease and 1820 control subjects) was reduced, for the dominant model (OR 0.70; 95% CI 0.62-0.81) and for the recessive model (OR 0.63; 95% CI 0.47-0.84).
Moreover, based on ethnicity, in the subgroup with MI: they reported an association for rs3856806 for the additive model (OR 2.68; 95% CI 1.10-6.54) and for the recessive model (OR 2.58; 95% CI 1.09-6.10), whereas for CAD they found a decreased risk for the additive model (OR 0.67; 95% CI 0.51-0.88) and for the dominant model (OR 0.69; 95% CI 0.61-0.79) . In the Korean Population Study, they did not find any statistically significant association between Pro12Ala polymorphism and CVD development (p = 0.824). In their prospective study, 267 subjects were included, divided into four groups, in the number of stenotic coronary arteries, the values of stenosis ≥50.% were considered significant. The percentage of patients with normal arterial lumen was 43.8%; 33.0% of patients had a stenosis of one coronary artery, 14.6% had a stenosis in two coronary arteries, and 8.6% had a stenosis of three coronary arteries . Similarly, Wan et al.  reported that there was a significant link between the C161T genotype and the vessels disease in a group of Chinese patients with CAD and T2DM (OR 1.22; 95% CI: 1.03-1.45, p = 0.019), but that there was no significant association with CAD risk (p = 0.695). In their study, a group of patients (CAD+T2DM) with CC genotype (70.3%) had severe stenosis >75.0% of one of the major coronary arteries. Moreover, they discovered that the C161T polymorphism was associated with adipose metabolism, which suggests that by modulating it, the risk of atherogenesis could be reduced in the group of patients with CAD and T2DM .
Epigenetics. So far, no study has reported about epigenetics of PPARγ in atherosclerosis in humans. However, epigenetic mechanisms have been implicated in the onset of atherosclerosis [21, 22, 23]. Previous research has shown a significant effect of epigenetic factors on gene expression, affecting adhesion, migration, differentiation of leukocytes, proliferation and migration of VSMCs, or all key processes in the onset and development of atherosclerosis. In addition to direct changes to human DNA, there are three other important epigenetic pathways that are important for the regulation of gene expression, which are DNA methylation, histone posttranslational modification and RNA-based mechanisms .
DNA methylation represents the covalent binding of the methyl group to the 5’ position of the cytosine, and plays a very important role in the organization of chromatin and in that way, leads to the silencing of certain genes, the complex formed is called 5’ methyl-cytosine . Key role in DNA methylation, which is mainly related to the CpG region, is played by three methyl transferases (DNMT1, DNMT3a and DNMT3b) with the S-adenosyl methionine donor of the methyl group . The exact mechanism of the development of atherosclerosis by changes in DNA methylation is not fully known, but many studies of high-fat diet-fed apoE null mice, human SMCs, and balloon-injured rabbit have shown a link between hypomethylation with the onset of atherosclerosis [24, 25, 26]. In these studies, hypomethylation was associated with increased expression of DNA methyltransferase (DNMT) in atherosclerotic lesions, removal of the methyl group increases the transcription activity. Migration and proliferation of VSMC are the central axis in the development of atherosclerosis . Lund et al. , showed in a study with ApoE null mice that changes in DNA methylation profiles might be markers of atherosclerosis in diabetics.
The four classes of histones (H2A, H2B, H3 and H4) form an octameric complex, with two copies of each of these four histones, and 147 bp chromosomal DNA wrapped on octameric complex, forming the onset and functional unit of chromatin nucleosomes. Cell DNA is packaged in chromatin . The unstructured N-terminal “tail” histone is subject to numerous modifications such as acetylation, methylation and phosphorylation . The most common histone modification is acetylation. With the enzyme histone acetyltransferase (HATs) and histone deacetylase (HDACs), gene transcription activity is monitored, HATs add the acetyl group to the histone tail, thereby activating the gene, and HDACs inhibiting, removing the acetyl group . Many studies show the relationship between acetylation and deacetylation status and atherosclerosis [25, 30].
Peroxisome proliferator-activated receptor induces the expression of the nuclear receptor in macrophages (LXRα), which increases the expression of ATP Binding Cassette Subfamily A Member 1 (ABCA1) (a member of the ABC transporter protein family) leading to the elimination of cholesterol from the macrophage. Deacetylation of PPARγ inhibits the pathway: PPARγ, LXRα, ABCA1, which leads to the blocking of cholesterol efflux, increased production of proinflammatory macrophages and the development of an inflammatory reaction, leading to the onset and development of atherosclerosis [31, 32].
According to Cao et al. , the HDAC9 expression is associated with the onset of atherosclerotic plaques in the arteries, the onset of stroke, and the increased expression of macrophages acts atherogenetic. In the study with LDLr [–/–] mice, the atherogenetic effect is reduced by deletion of HDCA9, which leads to an increase in macrophage cholesterol efflux and the prevention of the formation of foam cells, and reduces the production of inflammatory cells by translating macrophages from inflammatory M1 phenotype into an antiinflammatory M2 phenotype . This study demonstrates the important role of HDCA9 in the development of atherosclerosis, and the possibility of developing epigenetic therapy aimed at inhibiting HDCA9 isoforms in macrophages.
The third epigenetic model, the RNA-based mechanism, is relatively new. Currently the greatest attention of scientists attracts non coding RNA (ncRNA), including small RNAs . Considering the length of the fragment, we distinguished two main types of ncRNA: long ncRNA (>200 nucleotides) and short ncRNA (<200 nucleotides) and several subtypes that modulate gene expression . Short RNA [i.e, microRNA (miRNA)] performs genome repression by complementary binding to the 3’ or 5’ UTR (untranslated region) of targeted mRNA, activates the miRNA-induced silencing complex (miRISC) through which it silences gene expression . Long non coding RNA (LncRNA) has a wide range of effects in various processes from increasing to reducing gene expression in combination with other epigenetic enzymes, plays an important role in chromatin modulation, transcriptional and post-transcriptional regulation, cell apoptosis, etc. .
MicroRNA has a leading role in the regulation of ath-erosclerotic process . Previous studies of miRNA indicate a role in the prediction of certain diseases such as atherosclerosis, due to its role in protein production and the impact of one miRNA on several hundred target genes, so far about 1100 miRNA are known in humans . In the study, Zhao et al.  point out the important role of miR-613 in blocking the signaling pathway of PPARγ, LXRα and ABCA1, which leads to the stopping of cholesterol efflux and the development of atherosclerosis. Also, indicating that activated PPARγ increases the expression of LXRα and ABCA1, through the negative control of miR-613, acting anti-atherogenetic . In the Tampere Vascular Study, a significantly expression of miR-21, miR-210, miR-34a, and miR-146a/b was reported in aortic, carotid, and femoral atherosclerotic arteries in relation to non ath-erosclerotic left internal thoracic arteries . MicroRNA-21 and miRNA-34a show a significant relationship with the proliferation of VSMCs [38, 39]. MicroRNA-146a is associated with CADs and increased LDL release . The levels of ox-LDL play an important role in the onset of atherosclerosis, increasing the expression of miRNA-29b. These effects are achieved by repression of DNA methyl-transferase 3 Beta (DNMT3b), which increases cellular migration of VSMC through increased regulation of matrix metalloproteinase 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) . In the study Cipollone et al. , a significant difference in the expression of miRNA-100, miRNA-127, miRNA-145, miRNA-133a and miRNA-133b was found in the tissue of patients with endarterectomy of the carotid and control group. In short, this study, as well as the above studies, points to the role of miRNA in the onset of atherosclerosis, and highlights the possibility of using miRNAs as biomarkers for the onset and development of atherosclerosis.
Therapy. In vitro and in vivo studies have shown a positive effect of TZDs (tiazolidinediones) on the function and pharmacology of β-cells through the mechanism of mediated PPARγ, increasing the expression of PDX-1 (pancreatic duodenal homeobox) on β-cells in pre diabetics and T2DM patients . Clinical studies have shown that TZDs are PPARγ agonists that reduce inflammatory reactions, modulate two ATP-binding cassette transporter (ABCA1 and ABCG1) expression and inhibit key VSMC processes associated with atherosclerosis and protect blood vessels of T2DM patients . Several studies have shown positive effects of TZDs (Troglitazone, Pioglitazone) in T2DM patients on intima media thickness reduction and restenosis processes in T2DM patients with stent [42, 43, 44]. On the other hand, several studies describe the opposite effect of TZDs on PPARγ, which modulates adipocyte activity and leads to metabolic disorders and heart disease such as T2DM and CAD [16, 45]. So far, delivery of miR-150 may represent a potential approach to prevent macrophage foam cell formation in atherosclerosis by inhibition of the formation of macrophage foam cells through targeting adiponectin receptor 2 . Also, PPARγ agonists, by activating PPARγ, increase the concentration of adiponectin in plasma and expression of AdypoR2 in macrophages, and act anti-arteriogenic .
There are conflicting views on the role of PPARG polymorphisms at the onset of atherosclerosis. The reason may be the different genetic background of the observed population. The current, meta-analyzes of the effects of PPAR polymorphism on the development of atherosclerosis are heterogeneous with an unclear conclusion. We believe it is important to perform meta-analysis only in Caucasian or Asian populations, due to the impact of different genetic or epigenetic factors, which would contribute to a better understanding of the impact of these factors on the onset and the development of atherosclerosis in different populations. Some studies were done on a small number of subjects, some had a low average life-span, therefore larger and prospective studies with homogeneous groups had to be carried out. It is also necessary to examine in more detail the effect of polymorphisms investigated at the onset of atherosclerosis and their role in T2DM patients. Many studies have shown a significant effect of epigenetic factors in the development and onset of atherosclerosis but also other CVDs. However, the mechanism of origin is not adequately described, which must be accurately determined. Namely, epigenetic studies of atherosclerosis can offer very good therapeutic solutions for CVDs and their prevention. Due to the contrary attitudes about the effect of TZDs therapy on the processes of atherosclerosis and the occurrence of adverse effects in T2DM patients with CVD, it is necessary to decisively investigate mechanisms of action of PPARγ agonists in order to prevent the onset and progression of atherosclerosis in T2DM patients.
Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
Cai J-M, Hatsukami TS, Ferguson MS, Small R, Polissar NL, Yuan C. Classification of human carotid ath-erosclerotic lesions with in vivo multicontrast magnetic resonance imaging. Circulation. 2002; 106(11): 1368-1373.
Atherosclerosis. National Heart, Lung, and Blood Institute (NHLBI). Department of Health and Human Services, Bethseda, MD, USA, 2018 (https://www.nhlbi.nih.gov/health-topics/atherosclrerosis).
Roy S. Atherosclerotic cardiovascular disease risk and evidence-based management of cholesterol. N Am J Med Sci. 2014; 6(5): 191-198.
Hong YM. Atherosclerotic cardiovascular disease beginning in childhood. Korean Circ J. 2010; 40(1): 1-9.
Ammirati E, Moroni F, Norata GD, Magnoni M, Camici PG. Markers of inflammation associated with plaque progression and instability in patients with carotid atherosclerosis. Mediators Inflamm. 2015; 2015: 18329.
Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011; 473(7347): 317-325
Ross R. Atherosclerosis – An inflammatory disease. N Engl J Med. 1999; 340(2): 115-126.
Kruszynska YT, Mukherjee R, Jow L, Dana S, Paterniti JR, Olefsky JM. Skeletal muscle peroxisome proliferator-activated receptor-γ expression in obesity and non-insulin-dependent diabetes mellitus. J Clin Invest. 1998; 101(3): 543-548.
Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: Nuclear control of metabolism. Endocr Rev. 1999; 20(5): 649-688.
Hong C, Tontonoz P. Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors. Curr Opin Genet Dev. 2008; 18(5): 461-467.
Li AC, Glass CK. PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis. J Lipid Res. 2004; 45(12): 2161-2173.
Yongsakulchai P, Settasatian C, Settasatian N, Komanasin N, Kukongwiriyapan U, Cote ML, et al. Association of combined genetic variations in PPARγ, PGC-1α, and LXRα with coronary artery disease and severity in Thai population. Atherosclerosis. 2016; 248: 140-148.
Al-Shali KZ, House AA, Hanley AJGG, Khan HMRR, Harris SB, Zinman B, et al. Genetic variation in PPARG encoding peroxisome proliferator-activated receptor γ associated with carotid atherosclerosis. Stroke. 2004; 35(9): 2036-2040.
Wang L, Zhao L, Cui H, Yan M, Yang L, Su X. Association between PPARγ2 Pro 12Ala polymorphism and myocardial infarction and obesity in Han Chinese in Hohhot, China. Genet Mol Res Mol Res. 2012; 11(113): 2929-2938.
Flavell DM, Jamshidi Y, Hawe E, Pineda Torra I, Taskinen M-R, Frick MH, et al. Peroxisome proliferator-activated receptor α gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease. Circulation. 2002; 105(12): 1440-1445.
Li Y, Zhu J, Ding J. Association of the PPARγ2 Pro12Ala polymorphism with increased risk of cardiovascular diseases. Genet Mol Res. 2015; 14(144): 18662-18674.
Yan ZC, Zhu ZM, Shen CY, Zhao ZG, Ni YX, Zhong J, et al. Peroxisome proliferator-activated receptor γ C-161T polymorphism and carotid artery atherosclerosis in metabolic syndrome. Zhonghua Yi Xue Za Zhi. 2004; 84(7): 543-547.
Wang P, Wang Q, Yin Y, Yang Z, Li W, Liang D, et al. Association between peroxisome proliferator-activated receptor γ gene polymorphisms and atherosclerotic diseases: A meta-analysis of case-control studies. J Atheroscler Thromb. 2015; 22(9): 912-925.
Rhee EJ, Kwon CH, Lee WY, Kim SY, Jung CH, Kim BJ, et al. No Association of Pro12Ala polymorphism of PPAR-γ gene with coronary artery disease in Korean subjects. Circ J. 2007; 71(3): 338-342.
Wan J, Xiong S, Chao S, Xiao J, Ma Y, Wang J, et al. PPARγ gene C161T substitution alters lipid profile in Chinese patients with coronary artery disease and type 2 diabetes mellitus. Cardiovasc Diabetol. 2010; 9(1): 13.
Matouk CC, Marsden PA. Epigenetic regulation of vascular endothelial gene expression. Circ Res. 2008; 102(8): 873-887.
Yu J, Qiu Y, Yang J, Bian S, Chen G, Deng M, et al. DNMT1-PPARγ pathway in macrophages regulates chronic inflammation and atherosclerosis development in mice. Sci Rep. 2016; 6(1): 30053.
Miranda TB, Jones PA. DNA methylation: The nuts and bolts of repression. J Cell Physiol. 2007; 213(2): 384-390.
Hiltunen MO, Turunen MP, Häkkinen TP, Rutanen J, Hedman M, Mäkinen K, et al. DNA hypomethylation and methyltransferase expression in atherosclerotic lesions. Vasc Med. 2002; 7(1): 5-11.
Reddy MA, Natarajan R. Epigenetic mechanisms in diabetic vascular complications. Cardiovasc Res. 2011; 90(3): 421-429.
Laukkanen MO, Mannermaa S, Hiltunen MO, Aittomäki, Jänne J, Ylä-Herttuala S, et al. Gene ec-sod local hypomethylation in atherosclerosis found in rabbit. Arter Thromb Vasc Biol. 1999; 19(9): 2171-2178.
Lund G, Andersson L, Lauria M, Lindholm M, Fraga FM, Villar-Garea A, et al. DNA methylation polymorphisms precede any histological sign of atherosclerosis in mice lacking apolipoprotein E. J Biol Chem. 2004; 279(28): 29147-29154.
Kouzarides T. Chromatin modifications and their function. Cell. 2007; 128(4): 693-705.
Clayton AL, Hazzalin CA, Mahadevan LC. Review enhanced histone acetylation and transcription: A dynamic perspective. Mol Cell. 2006; 23(4): 289-296.
Doran AC, Meller N, McNamara CA. Role of smooth muscle cells in the initiation and early progression of atherosclerosis. Arterioscler Thromb Vasc Biol. 2008; 28(5): 812-819.
Chawla A, Boisvert WA, Lee C-H, Laffitte BA, Barak Y, Joseph SB, et al. A PPARγ-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell. 2001; 7(1): 161-171.
Cao Q, Rong S, Repa JJ, St. Clair R, Parks JS, Mishra N. Histone deacetylase 9 represses cholesterol efflux and alternatively activated macrophages in atherosclerosis development. Arterioscler Thromb Vasc Biol. 2014; 34(9): 1871-1879.
Cao Y, Lu L, Liu M, Li X-C, Sun R-R, Zheng Y, et al. Impact of epigenetics in the management of cardiovascular disease: A review. Eur Rev Med Pharmacol Sci. 2014; 18(20): 3097-3104.
Peschansky VJ, Wahlestedt C. Non-coding RNAs as direct and indirect modulators of epigenetic regulation. Epigenetics. 2014; 9(1): 3-12.
Toba H, Cortez D, Lindsey ML, Chilton RJ. Applications of miRNA technology for atherosclerosis. Curr Atheroscler Rep. 2014; 16(2): 386.
Zhao R, Feng J, He G. miR-613 Regulates cholesterol efflux by targeting LXRα and ABCA1 in PPARγ activated THP-1 macrophages. Biochem Biophys Res Commun. 2014; 448(3): 329-334.
Raitoharju E, Lyytikäinen L-P, Levula M, Oksala N, Mennander A, Tarkka M, et al. miR-21, miR-210, miR-34a, And miR-146a/b are up-regulated in human atherosclerotic plaques in the Tampere Vascular Study. Atherosclerosis. 2011; 219(1): 211-217.
Ma L, Yang J, Runesha HB, Tanaka T, Ferrucci L, Bandinelli S, et al. Genome-wide association analysis of total cholesterol and high-density lipoprotein cholesterol levels using the Framingham heart study data. BMC Med Genet. 2010; 11(1): 55.
Caolo V, Schulten HM, Zhuang ZW, Murakami M, Wagenaar A, Verbruggen S, et al. Soluble jagged-1 inhibits neointima formation by attenuating notchherp2 signaling. Arterioscler Thromb Vasc Biol. 2011; 31(5): 1059-1065.
Cipollone F, Felicioni L, Sarzani R, Ucchino S, Spigonardo F, Mandolini C, et al. A unique microRNA signature associated with plaque instability in humans. Stroke. 2011; 42(9): 2556-2563.
Gupta D, Jetton TL, Mortensen RM, Duan SZ, Peshavaria M, Leahy JL. In vivo and in vitro studies of a functional peroxisome proliferator-activated receptor γ response element in the mouse pdx-1 promoter. J Biol Chem. 2008; 283(47): 32462-32470.
Blaschke F, Caglayan E. Peroxisome proliferator-activated receptor γ agonists: Their role as vasoprotective agents in diabetes. Endocrinol Metab Clin North Am. 2006; 35(3): 561-574.
Minamikawa J, Tanaka S, Yamauchi M, Inoue D, Koshiyama H. Potent inhibitory effect of troglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab. 1998; 83(5): 1818-1820.
Takagi T, Yamamuro A, Tamita K, Yamabe K, Katayama M, Mizoguchi S, et al. Pioglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus: An intra-vascular ultrasound scanning study. Am Heart J. 2003; 146(2): 366.
Ruiz-Narváez EA, Kraft P, Campos H. Ala12 variant of the peroxisome proliferator-activated receptor-γ gene (PPARG) is associated with higher polyunsaturated fat in adipose tissue and attenuates the protective effect of polyunsaturated fat intake on the risk of myocardial infarction. Am J Clin Nutr. 2007; (86): 1238-1242.
Li J, Zhang S. microRNA-150 inhibits the formation of macrophage foam cells through targeting adiponectin receptor 2. Biochem Biophys Res Commun. 2016; 476(4): 218-224.
Chinetti G, Zawadski C, Fruchart J, Staels B. Expression of adiponectin receptors in human macrophages and regulation by agonists of the nuclear receptors PPARα, PPARγ, and LXR. Biochem Biophys Res Commun. 2004; 314(1): 151-158.