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The critical role of epigenetic mechanism in PM2.5-induced cardiovascular diseases

Abstract

Cardiovascular disease (CVD) has become the leading cause of death worldwide, which seriously threatens human life and health. Epidemiological studies have confirmed the occurrence and development of CVD are closely related to air pollution. In particular, fine particulate matter (PM2.5) is recognized as an important environmental factor contributing to increased morbidity, mortality and hospitalization rates among adults and children. However, the underlying mechanism by which PM2.5 promotes CVD development remains unclear. With the development of epigenetics, recent studies have shown that PM2.5 exposure may induce or aggravate CVD through epigenetic changes. In order to better understand the potential mechanisms, this paper reviews the epigenetic changes of CVD caused by PM2.5. We summarized the epigenetic mechanisms of PM2.5 causing cardiovascular pathological damage and functional changes, mainly involving DNA methylation, non-coding RNA, histone modification and chromosome remodeling. It will provide important clues for exploring the biological mechanisms affecting cardiovascular health.

Background

Fine particulate matter (PM2.5, the aerodynamic diameter less than 2.5 μm) in air pollution is a major public health problem worldwide. There is increasing evidence that air pollution affects public mortality [1]. According to the Global Burden of Disease (GBD) report, 7.5 % of global deaths (11.1 % in China) are attributable to air pollution [2, 3], and PM2.5 concentration increases by 10 µg/m³, the all-cause mortality rate will increase by 0.68 % [4]. Interestingly, recent studies have found long-term exposure to PM2.5 levels well below current World Health Organization standards, but the overall mortality rate of the population and the mortality rate of specific causes are still increasing [5]. There is a positive correlation between fine particulate matter and the negative health effects of humans such as respiratory diseases, cardiovascular diseases (CVD), and lung cancer. In recent years, the prevalence of CVD has continued to rise worldwide. In 2019, 6.2 million people in the 30 to 70 age group died from CVD [6]. The “Air Pollution and Cardiovascular Diseases” issued by the American Heart Association clearly pointed out that PM2.5 is one of the controllable risk factors leading to cardiovascular events [7]. Factors such as gender, age, and climate can affect the health effects of air pollution on the population, but epidemiological surveys show that CVD is the most closely related cause of death with air pollution [8]. Although the pollution of fine particulate matter has been actively controlled in China, it is still more serious compared with other areas [9].

In recent decades, investigators have conducted extensive studies on the relationship between air pollution and CVD, but the mechanism of PM2.5 causing cardiovascular damage is still not very clear. At present, a large number of clinical experiments and animal experiments have revealed relevant pathophysiological mechanisms, mainly including oxidative stress, systemic inflammation, vascular endothelial damage, mitochondrial damage, atherosclerosis, and changes in autonomic nerve function [10,11,12], among which oxidative stress may play an important role in the initiation and development of other mechanisms. Studies have shown that PM2.5 can induce and activate the production of reactive oxygen species and nitric oxide in cardiovascular endothelial cells [13, 14]. Its interaction triggers lipid peroxidation and changes the permeability and fluidity of cell membrane by oxidizing polyunsaturated fatty acids on the cell membrane. At the same time, the accumulation of oxidized lipids under the vascular endothelium and its secondary inflammation will promote the formation of plaques, causing atherosclerosis and impairing cardiovascular health.

Recently, a large number of evidences have suggested that epigenetics could be involved in the occurrence and development of CVD and play an important regulatory function in the cardiovascular system. Epigenetic changes are genetic changes in phenotype or gene expression when the DNA sequence has not changed, emphasizing the interaction between genes and the environment. Epigenetic modification imbalance is involved in the pathogenesis of cardiac hypertrophy and heart failure, regulating the transcriptional activity of transcription factors related to cardiac development [15, 16]. Studies have shown that epigenetic modifications may act as a bridge between oxidative stress and atherosclerosis [17]. External stimuli affect gene expression in endothelial cells, smooth muscle cells and macrophages. Subsequently, it may lead to epigenetic mutations, which eventually lead to the development of atherosclerosis [18,19,20].

In recent years, studies have found that epigenetic regulation is closely related to the cardiovascular hazards after PM2.5 exposure, such as histone acetylation modification, interferon γ methylation [21,22,23]. Exploring the epigenetic regularity of CVD caused by air pollution will help to understand the occurrence of diseases that interact with genes and the environment (Fig. 1a). The mechanism provides clues for research on the impact of air pollution on health. Gene regulation mediated by DNA methylation, m6A RNA methylation, non-coding RNA, histone modifications and chromosome remodeling are the most studied epigenetic mechanisms, which will be discussed in this review.

Fig. 1
figure1

Epigenetic mechanisms involved in PM2.5-induced CVD. a) PM2.5 induced CVD through epigenetic mechanisms; Mainly involved five aspects: (b) DNA methylation; (c) m6A RNA methylation; (d) Non-coding RNA; (e) Histone modification; (f) Chromosome remodeling

DNA methylation

DNA methylation is an epigenetic regulatory mechanism that has been extensively studied, and it plays an important role in gene transcription. DNA methylation means that under the catalysis of DNA methyltransferase (DNMTs), S-adenosylmethionine provides a methyl group, which is added to the 5-carbon atom of cytosine-phosphate-guanine (CpG) dinucleotide by covalent bond [24]. The establishment and maintenance of DNA methylation in mammals involve three types of DNMTs, namely DNMT1, DNMT3A, and DNMT3B2 [25], which are involved in DNA methylation to regulate normal biological functions, such as embryonic development, cell differentiation, and gene transcription. Recent studies have found that DNA methylation in gene promoter regions and important regulatory sequences will not only block the expression of downstream related genes, but may also have an activating effect [26]. The dynamic balance between methylation and demethylation is an important condition for maintaining the normal homeostasis of the body’s epigenetics. When this dynamic balance is broken, DNA is abnormally methylated, and some genes will be overexpressed or inhibited, leading to disease. DNA methylation is involved in the process and outcome of CVD. A study based on five population cohorts shows that gene methylation has a potential causal relationship with CVD [27]. Recent evidence links DNA methylation to cardiovascular hazards after PM2.5 exposure [28, 29], revealing that changes in DNA methylation may be a potential tool for CVD diagnosis.

More than 90 % of methylated CpG sites in the human genome occur in repetitive sequences, especially Alu sequences and long interspersed nuclear elements (LINE-1). The methylation levels of LINE-1 and Alu can be used as surrogate markers of overall genomic DNA methylation [30]. In normal differentiated cells, the LINE-1 promoter is hypermethylated and does not transpose, while it is activated in the early stages of germ cell development and embryonic development [31, 32]. Studies have found that LINE-1 hypomethylation is associated with increased morbidity and mortality of CVD [33]. In a randomized double-blind crossover trial of 35 healthy college students from Shanghai, China, researchers observed that exposure to PM2.5 in the air can induce a rapid decrease in DNA methylation in the repetitive elements LINE-1, Alu, and certain specific genes. An interquartile range increase (64 µg/m3) in PM2.5 was significantly associated with reduction of methylation in LINE-1 (1.44 %), one pro-inflammatory gene (CD40LG encoding soluble CD40 ligand, 9.13 %), two pro-coagulant genes (F3 encoding tissue factor, 15.20 %; SERPINE1 encoding plasminogen activator inhibitor-1, 3.69 %), and two pro-vasoconstriction genes (ACE encoding angiotensin-converting enzyme, 4.64 %; EDN1 encoding endothelin-1, 9.74 %). It was discovered for the first time that gene-specific hypomethylation plays an important role in the process of PM2.5 causing changes in biomarkers such as cardiovascular system inflammation, coagulation and vasoconstriction [28]. In the standard aging cohort, Andrea et al. used pyrosequencing to perform methylation sequencing on the peripheral blood samples of 704 elderly men. Assessing the impact of particulate matter exposure in different phases on methylation, it is found that methylation of repeated elements, such as LINE-1, was significantly reduced after short-term exposure to PM2.5. Furthermore, the researchers also found a positive correlation between LINE-1 hypomethylation and inflammation effects [34, 35]. In addition, a cross-sectional study conducted in Italy by Martina et al. showed that exposure to PM was negatively correlated with LINE-1 methylation in healthy women. In particular, they reported that the methylation level of LINE-1 decreased significantly with the increase of age [36].

A series of studies have provided valuable data. In an epidemiological study just released, researchers demonstrated that acute exposure to PM2.5 affects the methylation of pro-inflammatory genes and changes the function of cardiac parasympathetic regulation [21]. Interestingly, some studies have evaluated the relationship between DNA methylation and prenatal exposure. In a longitudinal cohort study, researchers have observed that prenatal exposure to PM10 and PM2.5 is related to changes in the methylation of a few gene promoters in the blood of newborns [37]. Some of these genes are also related to cardiovascular health outcomes in later childhood. Similarly, Russell and his colleagues found that C57BL/6J mice exposed to particulate matter during pregnancy had increased methylation of the HSD11B2 gene promoter and abnormal blood pressure in their offspring [38]. An epidemiological study on clock genes showed that exposure to high concentrations of PM2.5 can significantly change the methylation patterns of genes that regulate the circadian rhythm pathway, thereby increasing the risk of stroke events [39]. By contrast, a longitudinal panel study showed that a significant negative correlation between PM2.5 exposure and ACE methylation. Increased ACE protein accounted for 3.90~13.44 % of the elevated blood pressure by PM2.5. Therefore, it is speculated that hypomethylation of ACE gene may be one of the main epigenetic mechanisms of PM2.5 increasing blood pressure [29]. In addition, studies have analyzed the effects of PM2.5 on cardiomyocytes using methylation chips, and found that genes with methylation changes are significantly concentrated in pathways in regulation of apoptotic process, cell death and metabolic pathways [40]. This provides additional insights for studying the underlying mechanism of PM2.5-related heart disease.

In addition to nuclear DNA, PM2.5 also affects mitochondrial DNA (mtDNA) methylation. In a study of two groups of people with low and high exposure to environmental particles, the results suggest that locus-specific mtDNA methylation is correlated to PM exposures and mtDNA damage. Specifically, steel workers with high exposure to metal-rich PM exhibited higher levels of three specific mtDNA loci, i.e., the transfer RNA phenylalanine (MT-TF), 12 S ribosomal RNA (MT-RNR1) gene and “D-loop” control region [41]. Hyang-Min et al. found that mtDNA methylation in the blood of people exposed to PM2.5 is negatively correlated with PM2.5 concentration, and also found that the heart rate variability of subjects with higher mtDNA methylation levels is more likely to be affected by PM2.5 [42]. As we all know, heart rate variability is a very valuable indicator for predicting sudden cardiac death and arrhythmia events, and can be used to determine the condition and prevention of CVD [43]. In recent years, some studies have begun to pay attention to the relationship between PM and heart rate variability to speculate on important risk factors for CVD [44, 45].

In summary, the role of DNA methylation in the occurrence and development of CVD caused by air pollution exposure has received increasing attention. PM2.5 may lead to transcriptional activation of some CVD-related genes by promoting promoter demethylation (Fig. 1b). However, the relationship between PM2.5 exposure and DNA methylation has not reached a consistent conclusion. It is still necessary to further search for DNA methylation sites related to air pollution that leads to CVD as intervention targets to reduce the harm of PM2.5 exposure to the human body.

m6A RNA methylation

N6-methyladenosine (m6A) methylation is one of the most common epigenetic modifications of eukaryotic RNA [46]. It is a methylation modification formed by the 6th nitrogen atom of adenine through the catalysis of methylase, a newly discovered post-transcriptional gene expression regulation. The dynamic and reversible modification of m6A is accomplished by m6A methyltransferase, m6A demethylase, and m6A binding protein, which are separately described as ‘writers’, ‘erasers’ and ‘readers’ [47]. Messenger RNA (mRNA) is methylated under the catalysis of the ‘writer’, and this process can be reversed under the catalysis of the ‘eraser’. Moreover, the methylated mRNA can be recognized by the ‘reader’. The ‘writer’ methyltransferase is a complex composed of methyltransferase like 3 (METTL3), METTL14 and Wilms’ tumor 1-associating protein (WTAP) [48]. The main components of m6A demethylase include fat mass and obesity associated (FTO) genes and α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) [49, 50]. The components of m6A binding protein include members of the YTH domain protein family and heterogeneous nuclear ribonucleoprotein (HNRNP). Among them, the former includes two subtypes of YTH domain family protein (YTHDF) and YTH domain containing (YTHDC). The binding proteins of YTHDF subtypes are YTHDF1, YTHDF2 and YTHDF3, and the binding proteins of YTHDC subtypes are YTHDC1 and YTHDC2 [51]. Compared with DNA methylation, m6A can more directly regulate gene transcription and translation, realizing the rapid response to changes in the external environment. The researchers analyzed the expression of genes involved in the regulation of RNA methylation in people exposed to high or low concentrations of PM2.5. Expression of the writers METTL3 and WTAP were 1.27- and 2.11-fold higher in the high-PM2.5 group in comparison to the control group. Similarly, expression of the erasers FTO and ALKBH5 were 1.31- and 1.29-fold higher in the high-PM2.5 group in comparison to the control group, while the reader gene HNRNP was 1.52-fold higher in the high-PM2.5 group [52]. And this is the first study of the effect of environmental particulate matter on m6A RNA methylation. However, a cohort study examined the association of smoking and particulate matter with peripheral blood RNA m6A. Results showed that ever smoking was associated with a relative 10.7 % decrease in global m6A in men in comparison to nonsmokers. Surprisingly, global m6A was not associated with acute exposure to PM2.5 [53]. Even so, future studies should not ignore the association between m6A and PM2.5 exposure in vivo, and should also explore the impact of differences in the duration of PM2.5 exposure. In recent years, many studies have found that m6A RNA methylation plays an important role in the pathogenesis of heart failure, cardiac hypertrophy, aneurysm, pulmonary hypertension and vascular calcification [54,55,56]. Exposure to airborne particulate matter may cause dynamic changes in m6A methylation and demethylation, affecting gene transcription (Fig. 1c). Therefore, m6A is expected to serve as a bridge between PM2.5 exposure and CVDs. This provides a new perspective for the study of the mechanism of PM2.5 causing cardiovascular toxicity.

Noncoding RNA

Non-coding RNAs (ncRNAs) have important functional significance in human life, health and disease diagnosis and treatment. There are many types of ncRNAs classified by function. Among them, functional ncRNAs that are not translated into protein mainly include MicroRNA (miRNA), Long ncRNA (lncRNA) and Circular RNA (circRNA). ncRNAs participate in a variety of CVD and other diseases by controlling DNA methylation, influencing histone modification, and regulating mRNA transcription, stability and translation [57, 58]. Moreover, the abnormal expression of ncRNA can cause cell dysfunction, which can be used to reveal the relationship between environmental particulate matter and adverse cardiovascular events [59].

miRNAs play an important regulatory role in the biological processes of cell proliferation, apoptosis and differentiation [60]. Recent studies have found that PM2.5 can affect the expression of microribonucleic acid and produce potential biological effects [61]. In a study of elderly men exposed to environmental particulate matter for different periods of time, Serena and his colleagues found that PM2.5 was significantly negatively correlated with miR-1, miR-126, miR-146a, miR-222, and miR-9. It is worth noting that this effect is most obvious on the 7th day, suggesting that short-term exposure to air particles can cause rapid changes in miRNA [62]. Previous studies have shown that miR-1, miR-126, and miR-222 regulate important biological pathways in the cardiovascular system and participate in the occurrence and development of atherosclerosis and other CVD [63, 64]. Julian et al. tested the levels of miRNAs in the plasma of people exposed to airborne particulates to find the link between PM2.5 exposure and miRNA. Compared with people exposed to low levels of PM2.5, they observed decreased miR-133a-3p levels in 95 % of the subjects who exposed to high levels of PM2.5, in 85 % decreased miR-193b-3p levels, in 80 % increased miR-1224-5p levels, in 85 % decreased miR-433-3p levels, in 80 % decreased miR-145-5p levels, in 65 % decreased miR-27a-5p levels, in 60 % decreased miR-580-3p levels, in 55 % increased miR-3127-5p levels and in 75 % decreased miR-6716-3p levels. Among the rest, low expression of miR-133a-3p and miR-145-5p is associated with CVDs [65]. This down-regulation may cause serious consequences such as cardiac hypertrophy, severe fibrosis, and heart failure [66, 67]. In addition, a study of 55 healthy students exposed to indoor PM2.5 showed that PM2.5 may promote the pathological development of CVD by inducing systemic inflammation, coagulation, vasoconstriction, or the expression of cytokines in endothelial dysfunction. Among them, miRNAs play an important role in these regulatory processes [11].

Extracellular vesicles are rich in miRNAs, can be detected in readily available blood and body fluids, and are non-invasive [68], which is of great significance for the in-depth understanding of the pathogenesis of PM2.5-induced CVD. A study collected the sera of 22 veterans and confirmed that long-term exposure to PM2.5 upregulated miR-223-3p and miR-199a/b in extracellular vesicle miRNAs (evmiRNAs). It also suggests that they are involved in the process of oxidative stress, inflammation, atherosclerosis, and blood pressure [22, 69]. Recently, studies have shown that short-term exposure to particulate matter also increases the release of evmiRNAs [70], suggesting that evmiRNAs may become a marker of particulate matter susceptibility.

Previous studies have shown that lncRNA has an irreplaceable role in the normal physiological functions of the cardiovascular system [71]. Recently, more and more studies have provided evidence that lncRNA is involved in the pathogenesis of PM2.5-induced CVD. Pei et al. found that PM2.5 exposure can reduce the expression of LncRNA PEAMIR through in vivo and in vitro experiments [72]. It is worth noting that PEAMIR can effectively bind to key miRNAs in myocardial ischemia/reperfusion injury and exert an inhibitory effect. The down-regulation of PEAMIR increases the risk of myocardial ischemia/reperfusion injury. Other studies have shown that some lncRNAs play a regulatory role in PM2.5-mediated endothelial cell inflammation, such as NONHSAT247851.1. This finding helps to understand the occurrence and development of inflammatory vascular diseases [12]. Up to now, there are no reports about the role of circRNA in PM2.5-induced CVD. In summary, PM2.5 can up-regulate or down-regulate the expression of ncRNA in the body, and activate downstream related signal molecules, thus causing damage to the cardiovascular system (Fig. 1d).

Histone modification

Histones are a key factor in keeping chromatin in an inhibited or active conformation. Histone subunits are octamers composed of two molecules each of H2A, H2B, H3, and H4 [73], which can be tightly combined with acidic DNA and are the main components of the basic unit of eukaryotic chromatin. Histones can undergo modifications such as methylation, acetylation, phosphorylation, ubiquitination, etc., and they can aggregate in different modes to regulate chromatin structure. Unlike DNA methylation, the effects of histone modifications on gene expression may vary due to specific chemical modifications [74]. In recent years, more and more studies have confirmed that environmental factors are related to histone modifications. Abnormal histone modifications can in turn lead to many diseases, including CVD.

Studies have proved that histone methylation has a complicated relationship in maintaining the cell epigenome, and histone methylation modification is mediated by histone methyltransferases (HMTs) [75]. Zheng et al. observed the impact of traffic-derived particulate matter exposure on the health effects of truck drivers and found that PM is related to several types of histone H3 modifications in blood leukocytes. Namely H3 lysine 9 trimethylation (H3K9me3), H3 lysine 27 trimethylation (H3K27me3), H3 lysine 36 trimethylation (H3K36me3) and H3 lysine 9 acetylation (H3K9ac). The researchers also showed diminishing utility of these histone biomarkers of blood pressure throughout the day, particularly among individuals with occupational exposures [76]. This is the first epidemiological study to study the relationship between histone modification and blood pressure. Recently, histone acetylation and deacetylation are also considered to be one of the most important regulatory mechanisms that mediate cardiovascular development and myocardial damage. Histone deacetylation is involved in the regulation of gene transcription under stress or pathological conditions [77]. In a study of workers in an Italian steel factory, Cantone and his colleagues observed that PM in the air is directly proportional to the extracellular plasma histone modification H3K9ac, and showed that histone modification mediates PM2.5 to cause blood coagulation [78]. In addition, histone acetylation also plays an important role in PM2.5 exposure-induced cardiac hypertrophy events. Studies have found that in the hearts of PM2.5-exposed mice, the level of acetylated H3K9 protein increased significantly, leading to the up-regulation of hypertrophic transcription factors [23, 79]. These findings suggest that the imbalance between histone methylation and demethylation as well as acetylation and deacetylation increase the possibility of cardiac dysplasia and diseases related to the cardiovascular system under PM2.5 air pollution conditions (Fig. 1e).

Chromosome remodeling

Chromosome, as the genetic information of eukaryotic cells, is constantly damaged by various harmful factors in vivo and in vitro. People exposed to high levels of PM2.5 are at higher risk of developing certain diseases and living shorter lives. These negative effects may be caused by abnormal macromolecular changes caused by environmental pollutants, such as chromosomal aberrations [80]. Based on the analysis of baseline blood samples from 933 men ≥65 years of age from the prospective Cardiovascular Health Study, researchers have found that PM10 may increase white blood cell Y chromosomal mosaic deletions, a marker of genomic instability [81]. Studies have found a link between shorter telomere length and air pollution [82]. A longitudinal study found that pollution exposure is related to the length of chromosomal telomeres in children. When exposed to airborne particles, the telomeres in the cell will become longer and then shorter. In the later years of this group, the risk of chronic diseases will increase [83]. The accelerated erosion of telomere length leads to a decrease in the ability of cells to replicate in the heart or other tissues in the cardiovascular system, which may directly lead to the progression of CVD [84]. What’s more, the study found a stronger correlation between PM2.5 and shortened telomere length in white blood cells in girls than in boys during PM2.5 exposure [85]. These data suggest that PM2.5 may cause long-term changes such as chromosomal morphological abnormalities and shortening of telomeres on chromosomes (Fig. 1f), which have profound effects on cardiovascular morbidity and mortality in the population.

Conclusions

The epigenetic study in PM2.5-induced CVD is still preliminary, and it is urgent to verify the causal role of many epigenetic changes in particulate matter-related CVD. With the discovery of more types of epigenetic regulation in the human genome, the field of epigenetic regulation is still expanding. Many studies focused on CVD are encouraged to consider the potential role of epigenetics, which involves DNA methylation, histone modification and miRNA expression. In-depth discussion of the role of epigenetic regulation in CVD is the direction of future research, providing a theoretical basis for the treatment of CVD caused by environmental pollution.

Availability of data and materials

Not applicable.

Abbreviations

CVD:

cardiovascular disease

PM2.5 :

fine particulate matter

GBD:

Global Burden of Disease

DNMTs:

DNA methyltransferase

CpG:

cytosine-phosphate-guanine

LINE-1:

long interspersed nuclear elements

ACE:

angiotensin-converting enzyme

mtDNA:

mitochondrial DNA

MT-TF:

transfer RNA phenylalanine

MT-RNR1:

12 S ribosomal RNA

m6A:

N6-methyladenosine

METTL3:

methyltransferase like 3

WTAP:

Wilms’ tumor 1-associating protein

FTO:

fat mass and obesity associated

ALKBH5:

α-ketoglutarate dependent dioxygenase alkB homolog 5

HNRNP:

heterogeneous nuclear ribonucleoprotein

YTHDF:

YTH domain family protein

YTHDC:

YTH domain containing

ncRNAs:

non-coding RNAs

miRNA:

MicroRNA

lncRNA:

long ncRNA

circRNA:

circular RNA

evmiRNAs:

extracellular vesicle miRNAs

HMTs:

histone methyltransferases

H3K9me3:

H3 lysine 9 trimethylation

H3K27me3:

H3 lysine 27 trimethylation

H3K36me3:

H3 lysine 36 trimethylation

H3K9ac:

H3 lysine 9 acetylation

References

  1. 1.

    Wu X, et al. Evaluating the impact of long-term exposure to fine particulate matter on mortality among the elderly. Sci Adv. 2020;6(29):eaba5692.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Stanaway JD, et al. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet. 2018;392(10159):1923–94.

    Article  Google Scholar 

  3. 3.

    Naghavi M, et al. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet. 2017;390(10100):1151–210.

    Article  Google Scholar 

  4. 4.

    Liu C, et al. Ambient Particulate Air Pollution and Daily Mortality in 652 Cities. N Engl J Med. 2019;381(8):705–15.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Yu W, et al. The association between long-term exposure to low-level PM2.5 and mortality in the state of Queensland, Australia: A modelling study with the difference-in-differences approach. PLoS Med. 2020;17(6):e1003141.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Roth GA, et al. Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study. J Am Coll Cardiol. 2020;76(25):2982–3021.

    PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Robertson S, Miller MR. Ambient air pollution and thrombosis. Part Fibre Toxicol. 2018;15(1):1.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. 8.

    Al-Kindi SG, et al. Environmental determinants of cardiovascular disease: lessons learned from air pollution. Nat Rev Cardiol. 2020;17(10):656–72.

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    van Donkelaar A, et al. Global estimates of ambient fine particulate matter concentrations from satellite-based aerosol optical depth: development and application. Environ Health Perspect. 2010;118(6):847–55.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  10. 10.

    Fiordelisi A, et al. The mechanisms of air pollution and particulate matter in cardiovascular diseases. Heart Fail Rev. 2017;22(3):337–47.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Chen R, et al. Fine Particulate Air Pollution and the Expression of microRNAs and Circulating Cytokines Relevant to Inflammation, Coagulation, and Vasoconstriction. Environ Health Perspect. 2018;126(1):017007.

    PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Zhou C, et al. PM2.5-inducible long non-coding RNA (NONHSAT247851.1) is a positive regulator of inflammation through its interaction with raf-1 in HUVECs. Ecotoxicol Environ Saf. 2020;196:110476.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Montiel-Davalos A, et al. Oxidative stress and apoptosis are induced in human endothelial cells exposed to urban particulate matter. Toxicol In Vitro. 2010;24(1):135–41.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Weichenthal SA, Godri-Pollitt K, Villeneuve PJ. PM2.5, oxidant defence and cardiorespiratory health: a review. Environmental Health, 2013. 12(40).

  15. 15.

    Lei H, et al., The role and molecular mechanism of epigenetics in cardiac hypertrophy. Heart Fail Rev, 2020.

  16. 16.

    Ameer SS, Hossain MB, Knoll R. Epigenetics and Heart Failure. Int J Mol Sci, 2020. 21(23).

  17. 17.

    Traboulsi H, et al., Inhaled Pollutants: The Molecular Scene behind Respiratory and Systemic Diseases Associated with Ultrafine Particulate Matter. Int J Mol Sci, 2017. 18(2).

  18. 18.

    Carbone F, et al. Epigenetics in atherosclerosis: key features and therapeutic implications. Expert Opin Ther Targets. 2020;24(8):719–21.

    PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Neele AE, et al. Targeting epigenetics as atherosclerosis treatment: an updated view. Curr Opin Lipidol. 2020;31(6):324–30.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Shafi O. Switching of vascular cells towards atherogenesis, and other factors contributing to atherosclerosis: a systematic review. Thromb J. 2020;18:28.

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Tobaldini E, et al. Acute particulate matter affects cardiovascular autonomic modulation and IFN-gamma methylation in healthy volunteers. Environ Res. 2018;161:97–103.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Rodosthenous RS, et al. Extracellular vesicle-enriched microRNAs interact in the association between long-term particulate matter and blood pressure in elderly men. Environ Res. 2018;167:640–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Wu X, et al. In utero exposure to PM2.5 during gestation caused adult cardiac hypertrophy through histone acetylation modification. J Cell Biochem. 2019;120(3):4375–84.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Xu R, et al. Insights into epigenetic patterns in mammalian early embryos. Protein Cell. 2021;12(1):7–28.

    PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Hoang NM, Rui L. DNA methyltransferases in hematological malignancies. J Genet Genomics. 2020;47(7):361–72.

    PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Smith J, et al. Promoter DNA Hypermethylation and Paradoxical Gene Activation. Trends Cancer. 2020;6(5):392–406.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Ma J, Voortman T, Levy D. Whole blood DNA methylation signatures of diet are associated with cardiovascular disease risk factors and all-cause mortality. 2020.

  28. 28.

    Chen R, et al. DNA hypomethylation and its mediation in the effects of fine particulate air pollution on cardiovascular biomarkers: A randomized crossover trial. Environ Int. 2016;94:614–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Wang C, et al. Personal exposure to fine particulate matter and blood pressure: A role of angiotensin converting enzyme and its DNA methylation. Environ Int. 2016;94:661–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    Sae-Lee C, et al. DNA methylation patterns of LINE-1 and Alu for pre-symptomatic dementia in type 2 diabetes. PLoS One. 2020;15(6):e0234578.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Hata K, Sakaki Y. Identification of critical CpG sites for repression of L1 transcription by DNA methylation. Gene 1997: p. 227–234.

  32. 32.

    Jachowicz JW, et al. LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo. Nat Genet. 2017;49(10):1502–10.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Baccarelli A, et al. Ischemic heart disease and stroke in relation to blood DNA methylation. Epidemiology. 2010;21(6):819–28.

    PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Baccarelli A, et al. Rapid DNA methylation changes after exposure to traffic particles. Am J Respir Crit Care Med. 2009;179(7):572–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Bind MA, et al. Air pollution and markers of coagulation, inflammation, and endothelial function: associations and epigene-environment interactions in an elderly cohort. Epidemiology. 2012;23(2):332–40.

    PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Barchitta M, et al. Mediterranean Diet and Particulate Matter Exposure Are Associated With LINE-1 Methylation: Results From a Cross-Sectional Study in Women. Front Genet. 2018;9:514.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Breton CV, et al. Particulate matter, the newborn methylome, and cardio-respiratory health outcomes in childhood. Environ Epigenet. 2016;2(2):dvw005.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Morales-Rubio RA, et al. In utero exposure to ultrafine particles promotes placental stress-induced programming of renin-angiotensin system-related elements in the offspring results in altered blood pressure in adult mice. Part Fibre Toxicol. 2019;16(1):7.

    PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Cantone L, et al., Particulate Air Pollution, Clock Gene Methylation, and Stroke: Effects on Stroke Severity and Disability. Int J Mol Sci, 2020. 21(9).

  40. 40.

    Yang X, et al. Integrative analysis of methylome and transcriptome variation of identified cardiac disease-specific genes in human cardiomyocytes after PM2.5 exposure. Chemosphere. 2018;212:915–26.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Byun HM, et al. Effects of airborne pollutants on mitochondrial DNA methylation. Part Fibre Toxicol. 2013;10(18):18.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Byun HM, et al., Effects of Air Pollution and Blood Mitochondrial DNA Methylation on Markers of Heart Rate Variability. J Am Heart Assoc, 2016. 5(4).

  43. 43.

    Patterson PD, et al. Napping on the night shift and its impact on blood pressure and heart rate variability among emergency medical services workers: study protocol for a randomized crossover trial. Trials. 2021;22(1):212.

    PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Niu Z, et al. Acute effect of ambient fine particulate matter on heart rate variability: an updated systematic review and meta-analysis of panel studies. Environ Health Prev Med. 2020;25(1):77.

    PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Wang F, et al. The relationship between exposure to PM2.5 and heart rate variability in older adults: A systematic review and meta-analysis. Chemosphere. 2020;261:127635.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Roundtree IA, et al. Dynamic RNA Modifications in Gene Expression Regulation. Cell. 2017;169(7):1187–200.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Meyer KD, et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3’ UTRs and near stop codons. Cell. 2012;149(7):1635–46.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Wang Y, et al. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat Cell Biol. 2014;16(2):191–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Jia G, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011;7(12):885–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Zheng G, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013;49(1):18–29.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    Wang X, et al. N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency. Cell. 2015;161(6):1388–99.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Cayir A, et al. Exposure to environmental toxicants reduces global N6-methyladenosine RNA methylation and alters expression of RNA methylation modulator genes. Environ Res. 2019;175:228–34.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53.

    Kupsco A, et al. Associations of smoking and air pollution with peripheral blood RNA N(6)-methyladenosine in the Beijing truck driver air pollution study. Environ Int. 2020;144:106021.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Song D, et al. Role of N(6)-Methyladenosine RNA Modification in Cardiovascular Disease. Front Cardiovasc Med. 2021;8:659628.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Zhao K, et al. Epigenetic role of N6-methyladenosine (m6A) RNA methylation in the cardiovascular system. J Zhejiang Univ Sci B. 2020;21(7):509–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Dorn LE, et al. RNA epigenetics and cardiovascular diseases. J Mol Cell Cardiol. 2019;129:272–80.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Gao J, et al. Autophagy in cardiovascular diseases: role of noncoding RNAs. Mol Ther Nucleic Acids. 2021;23:101–18.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Videira RF, da Costa Martins PA, Falcao-Pires I. Non-Coding RNAs as Blood-Based Biomarkers in Cardiovascular Disease. Int J Mol Sci, 2020. 21(23).

  59. 59.

    Wang Y, Tang M. Integrative analysis of mRNAs, miRNAs and lncRNAs in urban particulate matter SRM 1648a-treated EA.hy926 human endothelial cells. Chemosphere. 2019;233:711–23.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Wojciechowska A, Braniewska A, Kozar-Kaminska K. MicroRNA in cardiovascular biology and disease. Adv Clin Exp Med. 2017;26(5):865–74.

    PubMed  Article  PubMed Central  Google Scholar 

  61. 61.

    Tumolo MR, et al., The expression of microRNAs and exposure to environmental contaminants related to human health: a review. Int J Environ Health Res, 2020: p. 1–23.

  62. 62.

    Fossati S, et al. Ambient particulate air pollution and microRNAs in elderly Men. Epidemiology. 2013;25:68–78.

    Article  Google Scholar 

  63. 63.

    Satrauskiene A, et al., Mir-1, miR-122, miR-132, and miR-133 Are Related to Subclinical Aortic Atherosclerosis Associated with Metabolic Syndrome. Int J Environ Res Public Health, 2021. 18(4).

  64. 64.

    Hromadnikova I, et al. Postpartum profiling of microRNAs involved in pathogenesis of cardiovascular/cerebrovascular diseases in women exposed to pregnancy-related complications. Int J Cardiol. 2019;291:158–67.

    PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    Krauskopf J, et al. The human circulating miRNome reflects multiple organ disease risks in association with short-term exposure to traffic-related air pollution. Environ Int. 2018;113:26–34.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Care A, et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med. 2007;13(5):613–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67.

    Chung DJ, et al. Nelumbo nucifera leaf polyphenol extract and gallic acid inhibit TNF-alpha-induced vascular smooth muscle cell proliferation and migration involving the regulation of miR-21, miR-143 and miR-145. Food Funct. 2020;11(10):8602–11.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68.

    Liu T, et al. EVmiRNA: a database of miRNA profiling in extracellular vesicles. Nucleic Acids Res. 2019;47(D1):D89–93.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. 69.

    Rodosthenous RS, et al. Ambient particulate matter and microRNAs in extracellular vesicles: a pilot study of older individuals. Part Fibre Toxicol. 2016;13:13.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. 70.

    Pergoli L, et al. Extracellular vesicle-packaged miRNA release after short-term exposure to particulate matter is associated with increased coagulation. Part Fibre Toxicol. 2017;14(1):32.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. 71.

    Wang Y, Sun X. The functions of LncRNA in the heart. Diabetes Res Clin Pract. 2020;168:108249.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  72. 72.

    Pei YH, et al. LncRNA PEAMIR inhibits apoptosis and inflammatory response in PM2.5 exposure aggravated myocardial ischemia/reperfusion injury as a competing endogenous RNA of miR-29b-3p. Nanotoxicology. 2020;14(5):638–53.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  73. 73.

    Berger SL. The complex language of chromatin regulation during transcription. Nature. 2007;447(7143):407–12.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74.

    Shahbazian MD, Grunstein M. Functions of site-specific histone acetylation and deacetylation. Annu Rev Biochem. 2007;76:75–100.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    Husmann D, Gozani O. Histone lysine methyltransferases in biology and disease. Nat Struct Mol Biol. 2019;26(10):880–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Kresovich JK, et al. Histone 3 modifications and blood pressure in the Beijing Truck Driver Air Pollution Study. Biomarkers. 2017;22(6):584–93.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Wang Z, Zhao YT, Zhao TC. Histone deacetylases in modulating cardiac disease and their clinical translational and therapeutic implications. Exp Biol Med (Maywood). 2021;246(2):213–25.

    CAS  Article  Google Scholar 

  78. 78.

    Cantone L, et al. Extracellular histones mediate the effects of metal-rich air particles on blood coagulation. Environ Res. 2014;132:76–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Li R, et al. Effects of PM2.5 exposure in utero on heart injury, histone acetylation and GATA4 expression in offspring mice. Chemosphere. 2020;256:127133.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  80. 80.

    Rossner P Jr, et al. Analysis of biomarkers in a Czech population exposed to heavy air pollution. Part II: chromosomal aberrations and oxidative stress. Mutagenesis. 2013;28(1):97–106.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  81. 81.

    Wong JYY, et al. Outdoor air pollution and mosaic loss of chromosome Y in older men from the Cardiovascular Health Study. Environ Int. 2018;116:239–47.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Zhao B, et al. Air pollution and telomere length: a systematic review of 12,058 subjects. Cardiovasc Diagn Ther. 2018;8(4):480–92.

    PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Walton RT, et al. Air pollution, ethnicity and telomere length in east London schoolchildren: An observational study. Environ Int. 2016;96:41–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  84. 84.

    Grahame TJ, Schlesinger RB. Oxidative stress-induced telomeric erosion as a mechanism underlying airborne particulate matter-related cardiovascular disease. Part Fibre Toxicol. 2012;9:21.

    PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Rosa MJ, et al. Association between prenatal particulate air pollution exposure and telomere length in cord blood: Effect modification by fetal sex. Environ Res. 2019;172:495–501.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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This work was supported by National Natural Science Foundation of China (91943301, 92043301), Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (KZ202110025040) and Beijing Outstanding Talent Training Program.

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Sun, Q., Ren, X., Sun, Z. et al. The critical role of epigenetic mechanism in PM2.5-induced cardiovascular diseases. Genes and Environ 43, 47 (2021). https://doi.org/10.1186/s41021-021-00219-w

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Keywords

  • PM2.5
  • Cardiovascular disease
  • DNA methylation
  • m6A RNA methylation
  • Non-coding RNA
  • Histone modification
  • Chromosome remodeling