Hypertensive epigenetics: from DNA methylation to microRNAs

Subjects

Abstract

The major epigenetic features of mammalian cells include DNA methylation, posttranslational histone modifications and RNA-based mechanisms including those controlled by small non-coding RNAs (microRNAs (miRNAs)). An important aspect of epigenetic mechanisms is that they are potentially reversible and may be influenced by nutritional–environmental factors and through gene–environment interactions. Studies on epigenetic modulations could help us understand the mechanisms involved in essential hypertension and further prevent it’s progress. This review is focused on new knowledge on the role of epigenetics, from DNA methylation to miRNAs, in essential hypertension.

Introduction

Essential hypertension is a disease that develops due to complex interactions of susceptibility genes and environmental factors.1 It is estimated that the overall prevalence of hypertension appears to be around 30%–45% of the general population, with a steep increase with aging.2 The number of adults with hypertension in 2025 is predicted to increase by ~60% to a total of 1.56 billion, particularly projected in economically developing countries.3 As we know, essential hypertension is a significant risk factor for coronary artery disease, stroke and kidney disease.4, 5 Many pathophysiologic factors have been implicated in the genesis of essential hypertension such as increased sympathetic nervous system activity, overproduction of sodium retention hormones and increased or inappropriate renin secretion.6

Improved techniques of genetic analysis, especially genome-wide linkage analysis, have enabled deep search for genes. Most promising findings suggest that there are many genetic loci, each with small effects on blood pressure in the general population.7 Many genes of small effect, which display effect modification in the presence of some environmental factors, are responsible for the etiology of human hypertension.8 However, the genetic contribution to blood pressure variation among individuals is estimated to range from 30% to 50%.8 Epigenetic regulation, which can alter gene expression without changing the nucleotide base sequence of gene, may result from environment–gene interactions.9 Epigenetics is emerging as one of important regulators of transcription of specific genes involved in the pathogenesis of essential hypertension.

Definition of epigenetics

Epigenetic phenomena are defined as heritable mechanisms that establish and maintain mitotically stable patterns of gene expression without modifying the base sequence of DNA.10 The field can be broadly categorized into three areas: DNA base modifications (including cytosine methylation and cytosine hydroxymethylation), posttranslational modifications of histone proteins and RNA-based mechanisms that operate in the nucleus, which collectively enable the cell to respond quickly to environment changes (Figure 1).11, 12

Figure 1
figure1

The three areas of epigenetics: DNA base modifications (including DNA methylation and DNA hydroxymethylation), histone modification and RNA-based mechanisms (including long non-coding RNAs and short RNAs).

Gene-specific DNA methylation and essential hypertension

DNA methylation is a covalent modification in which the 5′-position of cytosine is methylated in a reaction catalyzed by DNA methyltransferases with S-adenosyl-methionine as the methyl donor.13 In mammals, this modification occurs exclusively at the C5 position of cytosine residues (5-methylcytosine) and predominantly in the context of CpG dinucleotides.14 However, non-CpG methylation in adult mammalian tissues, such as CpA, CpT and CpNpG sites, has been observed.11, 15 The main function of DNA methylation is to modulate the expression of the genetic information, by modifying the accessibility of DNA to the transcriptional machinery.10

HSD11B2 gene methylation

The HSD11B2 gene, encoding the kidney isoenzyme 11β-hydroxysteroid dehydrogenase, is a candidate for essential hypertension.16 The enzyme 11βHSD type 2 (11βHSD2) isoform binds NAD with high affinity and catalyzes the dehydrogenation of 11β-hydroxyglucocorticoids.17 The absence of 11βHSD2 prevents conversion of cortisol into cortisone, resulting in a rise in intracellular cortisol levels, overstimulation of the mineralocorticoid receptor and excessive sodium reabsorption (Figure 2).18 The activity of the enzyme 11βHSD2 can be indirectly evaluated by measuring urinary tetrahydrocortisol/tetrahydrocortisone ratio; an increase in urinary tetrahydrocortisol/tetrahydrocortisone ratio indicates decreased 11βHSD2 activity.19

Figure 2
figure2

Physiological function of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2).

Epigenetic modulation of the HSD11B2 gene has been demonstrated in both rodent model and cultured human cell lines.20 CpG islands covering the promoter and exon 1 of HSD11B2 are found to be densely methylated in tissues and cell lines with low expression.20 Demethylation induced by 5-aza-2′-deoxycytidine and procainamide enhances the transcription and activity of the 11βHSD2 enzyme in human cells in vitro and in rats in vivo.20 Moreover, methylation of recognition sequences of transcription factors, including those for Sp1/Sp3, Arnt and nuclear factor 1, diminishes their DNA-binding activity.20 In a human study, the HSD11B2 promoter region has an elevated methylation status in glucocorticoid-treated patients who develop hypertension.21 Furthermore, the higher DNA methylation at HSD11B2 promoter sites parallels a higher urinary tetrahydrocortisol/tetrahydrocortisone ratio.21 These present results suggest DNA methylation is a major mechanism for the regulation of HSD11B2 gene expression by modulating the binding of transcription factors and has a role in the pathogenesis of hypertension.

ACE gene methylation

Two isoforms, somatic and germinal angiotensin-converting enzyme (ACE), are transcribed from two alternate promoters within a single gene termed ace-1.22 Somatic ACE isoform is a key regulator of blood pressure. It catalyzes the conversion of angiotensin I into physiologically active angiotensin II, a substance with potent vasopressive properties, and degrades the vasodilator bradykinin.23, 24 In mice, inhibition of ACE activity reduces angiotensin II levels in blood and tissues.25 In clinical practice, ACE inhibitors are of established benefit for the treatment of hypertension.

Two CpG islands are identified in the human ace-1 gene 3 kb proximal promoter region and their methylation abolishes the luciferase activity of ace-1 promoter/reporter constructs transfected into human liver (HepG2), colon (HT29), microvascular endothelial (HMEC-1) and lung (SUT) cell lines.26 Inhibition of DNA methylation by 5-aza-2′-deoxycytidine stimulates sACE mRNA expression specifically in in vitro cell type and in vivo tissue type.26 5-Aza-2′-deoxycytidine induces an increase (~25 mm Hg) in blood pressure after a single injection in the rat, associated with an elevated sACE expression in the lungs and the liver of treated rats, and a substantial and unexpected decrease of plasma angiotensin II levels.26 In low birth-weight children, DNA methylation status in three CpG sites (nucleotide positions +555, +561 and +563) from the ACE gene promoter is decreased, simultaneously with an increase in the ACE protein activity and high blood pressure levels.27 Furthermore, systolic blood pressure levels and ACE protein activity are inversely correlated with the degree of DNA methylation.27 Epigenetic regulation of ACE gene expression might be crucial in the control of blood pressure through angiotensin II-dependent pathways.

NKCC1 gene methylation

The solute carrier family 12 member 2 (SLC12A2), which is also called Na+-K+-2Cl cotransporter 1 (NKCC1), mediates the symport of sodium, potassium and chloride.28 NKCC1 is expressed in most of the cells including vascular smooth muscle cells (VSMCs), endothelial cells, cardiomyocytes, neurons, glial cells and blood cells.28 Under baseline conditions ([Na+]o>>[Na+]i and [Cl]o2>>[Cl]i2), NKCC provides inwardly directed net ion flux and maintenance of [Cl]i above values predicted by the Nernst equilibrium potential.28 In VSMCs, the contribution of K permeability (PK) to resting membrane potential (Em) is somewhat similar with that of Cl permeability (PCl).29 NKCC-mediated modulation of [Cl]i affects Em-dependent and Em-independent VSMC contraction.30 High-ceiling diuretics, inhibitors of NKCC1, decrease [Cl]i, hyperpolarize VSMCs, attenuate the activation of levo-type Ca2+ channels and reduce smooth muscle contractions.31 NKCC1 has a role in the onset of high blood pressure, via an increased cytosolic chloride accumulation in VSMCs.32

In cultured cells, WNK1 (with-no-lysine 1) is activated by either hyperosmotic stress or hypotonic low Cl conditions.33, 34 SPAK (STE20/SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1) are physiological substrates for WNK1, conditions that stimulate WNK1 activation in cells induces the activation of endogenous SPAK and OSR1.35 CCT domain of SPAK and OSR1 interacts with RFXV motifs on NKCC1 as well as WNK1 and WNK4 with high affinity.36 Wnk1+/− mice exhibit a significant alteration in blood pressure and vasoconstricting responses specific to α1-adrenergic vasoconstrictors in both conductance and resistive arteries.37 WNK1 is a major protein in the vasoconstriction pathway linking α1-adrenergic receptors and its downstream effectors SPAK/OSR1 and NKCC1 (Figure 3).

Figure 3
figure3

The WNK-SPAK/OSR1 signaling pathway by which the Na+-K+-2Cl cotransporter 1 (NKCC1) is regulated and affects vascular contraction in essential hypertension.

Lee et al.38 analyzed promoter methylation of the NKCC1 gene (official gene symbol SLC12A2) in male Wistar Kyoto (WKY) and spontaneously hypertensive rat (SHR). They revealed that NKCC1 promoter is hypomethylated in the aorta and hearts of SHR, that is, coincided with upregulation of NKCC1 mRNA and protein compared with WKY.38 Furthermore, the promoter region of NKCC1 in WKY is methylated with age, while that in SHRs remains hypomethylated during postnatal development of hypertension.39 The activity of DNA methyltransferases after development of hypertension is about threefold higher in WKY than SHR, which is in accordance with the methylation status on the NKCC1 promoter of WKY and SHR.39 Phenylephrine-induced vasoconstrictions are significantly attenuated by bumetanide (an inhibitor of NKCC1) in both isolated aortae and second-order mesenteric artery of SHR than those of WKY.38 This declined effect of phenylephrine by bumetanide is partially caused by higher expression of NKCC1 mRNA and protein in SHR.38 These data provide new insights into the epigenetic mechanism of the action of NKCC1 that may contribute to the development of hypertension.

ADD1 gene methylation

ADD1 (α-adducin) gene, a candidate gene for essential hypertension,40 encodes one of adducin subunits and is expressed in most tissues.41 Adducin selectively binds to the spectrin–actin network and recruits additional spectrins to actin filaments.41 The actin-based cytoskeleton interacts with the band 3-anion exchanger, the epithelial Na channels, the Na-K-Cl cotransport and the Na-K ATPase.42 Cells transfected with Milan hypertensive rats adducin have shown a significant increase in Na–K pump activity at Vmax and of Na–K pump units compared with cells carrying the Milan normotensive strain adducin.43 Thus, adducin modulates the surface expression of multiple transporters and ion pumps, and regulates cellular signal transduction and cytoplasmic ion transport.40

An association study with 33 hypertensive patients and 28 age- and gender-matched controls showed that DNA methylation levels are closely correlated among CpG2–5, and ADD1 CpG2–5 methylation levels are significantly associated with essential hypertension.44 However, ADD1 CpG1 methylation level is significantly associated with essential hypertension in females but not in males, and lower levels of ADD1 CpG2–5 methylation is associated with increased risk of essential hypertension in males.44

ADRB1 gene methylation

The sympathetic nervous system has a crucial role in the regulation of blood pressure, mainly through activating α- and β-adrenergic receptors in the effector organs, including the heart, kidney and the blood vessels.45 The β1-adrenoreceptor (ADRB1) gene is one of the hypertension-susceptibility candidates as a pivotal mediator of signal transduction in cardiac, vascular, endocrine and sympathetic adrenal systems.46 The human ADRB1, which mediates the actions of catecholamines in the sympathetic nervous system, is a key cell surface signaling protein expressed in multiple organs and tissues including the heart, kidney, brain and the pineal gland.47

The ADRB1 promoter has many methylated sites.48 According to the animal model experiment, SHRs that had better antihypertensive response to metoprolol showed a lower level of DNA methylation modification and a higher expression of ADRB1 in their myocardial tissues.48 In SHRs, hypomethlation of the ADRB1 promoter is likely to improve the antihypertensive efficacy of metoprolol.48 Thus, the epigenetic molecular mechanism could lead to ADRB1 gene-directed therapy.

αENaC gene methylation

The epithelial sodium channel (ENaC) consists of three homologous subunits α, β and γ, which are encoded by the sodium channel, non-voltage-gated 1α (Scnn1a), β (Scnn1b) and γ (Scnn1G) genes, respectively.49 ENaC is expressed in the apical membrane of salt-absorbing epithelia of kidney, distal colon and lung airways.49 ENaC has a major role in Na+ reabsorption in the distal tubule, and hence the regulation of Na+ balance, extracellular fluid volume and blood pressure.50 Of the three ENaC subunits, αENaC appears to be critical to the overall salt balance. Mice with targeted inactivation of αENaC in the connecting tubule/collecting duct exhibit severe renal salt wasting characteristic of a pseudohypoaldosteronism type I phenotype.51 Aldosterone is a major regulator of epithelial Na+ absorption and acts in large part through ENaC induction in the renal collecting duct.52, 53 In this region, aldosterone administration or hyperaldosteronism induced by a low-Na+ diet increases αENaC gene transcription, without increasing β- or γ-subunit expression.54

A CpG island near the transcription start site of the αENaC promoter is regulated by the control of promoter methylation status (Figure 4). Under basal conditions, cytosine methylation in this region of the αENaC promoter is evident in mIMCD3 cells.55 5-Aza-2′-deoxycytidine-mediated promoter demethylation enhances Sp1 binding to, and transactivation of the αENaC promoter, thus increases αENaC mRNA expression.55 Aldosterone reprograms the methylation status of the R3 subregion of the αENaC promoter from a predominance of 5-methylcytosine under basal conditions to a predominance of 5-hydroxymethylcytosine.55 This change is accompanied by depletion of DNMT3b at this subregion and enhances enrichment of Tet2.55 Aldosterone treatment disperses DNMT3b from the αENaC R3 subregion and recruits Tet2 to convert 5-methylcytosine to 5-hydroxymethylcytosine at this subregion, to contribute to the derepression of αENaC transcription.55 Aldosterone-dependent demethylation of the αENaC promoter also facilitates Sp1 binding to the promoter, to allow further transactivation of the αENaC gene.55

Figure 4
figure4

Two epigenetic mechanisms of αENaC for derepression: disruption of Dot1a-mediated histone H3K79 methylation and the targeted demethylation of the αENaC promoter.

Histone modification in essential hypertension

Genomic DNA is compacted in the chromatin, whose basic unit is the nucleosome that is formed by an octamer of histone proteins H2A, H2B, H3 and H4. Posttranslational modifications occurring at residues in N-terminal tail of histone include phosphorylation, sumoylation, biotinylation, acetylation and methylation, and control the dynamics of chromatin to regulate gene expression.56

Acetylation modification

The acetylation/deacetylation balance among most of studies is one of histone-related epigenetic mechanisms, and histone–histone or histone–DNA interplay regulates gene expression.57 Histone H3 is acetylated by histone acetyltransferase at different lysine positions and the site is indicative of different events; for example, acetylation at lysine-14 indicates active transcription of DNA into RNA.58

Acetylation modification in the neurons of area postrema

Melatonin secretion from pineal gland may be disturbed by almost all environmental factors, such as light and temperature.59 Melatonin as an appropriate mediator transfers the environmental information to the area postrema (AP), where the high levels of nuclear melatonin receptors are located.60 The rostral ventrolateral medulla neurons receive excitatory input from AP, which responds to blood and cerebrospinal fluid signals, and provide excitatory output to preganglionic neurons in the intermediolateral cell column of the spinal cord, which provide sympathetic output to target organs.60 Treatment with physiological (nanomolar) concentrations of melatonin for 24 h was reported to increase the acetylation of histone H3 in progenitor cells, augment neurite-like extensions and promote mRNA expression of nestin, a neural stem cell marker.61 Melatonin was also reported to increase the mRNA expression of various other histone acetyltransferase isoforms.61 Environmental stressors affect melatonin secretion and cause epigenetic modifications in the neurons of AP, shifting the blood pressure set-point signal of the AP to a higher pressure.60 This signal may then operate through efferent projections to key medullary sympathetic nuclei in the rostral ventrolateral medulla, thereby increasing brainstem sympathetic outflow and explaining the long-term alterations in sympathetic activity associated with essential hypertension.60, 62 The axis of pineal gland–AP–rostral ventrolateral medulla participates in adaptive responses to environmental and internal stressors and the pathogenesis of essential hypertension.

Acetylation modification at WNK4 promoter region

WNK4 is a member of the serine–threonine protein kinase family. Human WNK4 (hWNK4) expresses mainly in the kidney and partly in polarized epithelia.63 It acts as a multifunctional regulator of diverse ion transporters, including NaCl cotransporter and renal outer medullary K+ channel, and can vary the balance between NaCl reabsorption and K+ secretion to maintain integrated homeostasis.64 Therefore, it may be involved in pathophysiological processes of fluid and electrolyte perturbations and hypertension.63

It has been demonstrated that glucocorticoid downregulates hWNK4 expression through the negative glucocorticoid responsive elements.65 The β2-adrenergic receptor stimulation leads to cyclic adenosine monophosphate-dependent inhibition of histone deacetylase-8 activity in the kidney and increases histone acetylation in the WNK4 promoter region, resulting in transcriptional modulation dependent on glucocorticoid receptors binding to a negative glucocorticoid responsive element in this region.66 Trichostatin A, a histone deacetylase inhibitor, upregulates hWNK4 mRNA and protein expression within the hWNK4 promoter in HEK293 cells.67 In rat models, salt loading suppresses renal WNK4 expression, activates Na+-Cl cotransporter and induces salt-dependent hypertension.66 These findings suggest epigenetic modulation of WNK4 transcription in the development of salt-sensitive hypertension.

Histone modification at αENaC promoter region

Dot1a (disruptor of telomeric silencing alternative splice variant ‘a’) is a lysine methyltransferase that methylates the histone H3K79 site of nucleosomes and disrupts the process of silencing genes located in the telomeric regions of chromosomes during DNA repair for maintaining telomere length.49 Af9, the fused mixed-lineage leukemia and acute lymphoblastic leukemia gene mapped to chromosome 9 (Af9), produces a sequence-specific DNA-binding protein that binds to Dot1a.49

Af9, a putative transcription factor, physically and functionally interacts with Dot1a to form a nuclear repressor complex, which, via direct or indirect binding to specific sites in the αENaC promoter, regulates histone H3K79 methylation at these sites and represses basal transcription of αENaC.68 Aldosterone downregulates the Dot1a–AF9 complex, at least in part by inhibiting Dot1 and AF9 expression, leading to targeted histone H3K79 hypomethylation and transcriptional activation of αENaC.68 Furthermore, Af9 has been identified as a physiologic target for Sgk1 (serum- and glucocorticoid-induced kinase-1) phosphorylation, and Sgk1 as a novel component and negative regulator of the Dot1a-Af9 complex.53 Aldosterone not only downregulates the abundance of the components of the Dot1a-Af9 complex but also (via Sgk1-mediated phosphorylation of Af9) weakens their interaction, leading to targeted histone H3K79 hypomethylation at the αENaC promoter and derepression of αENaC transcription.53 The Dot1a-Af9 pathway is thus likely to influence the expression of this gene regulating sodium transport (permeability), contributing to renal fibrosis and genetic predilections for salt-sensitive hypertension.69 AF17 competes with AF9 for interaction with Dot1a and antagonizes the epigenetic repressor effects of Dot1a-AF9 on αENaC transcription, and augments αENaC-mediated Na+ transport under basal conditions.70 The positive regulatory effect of AF17 on αENaC transcription appears to involve, at least in part, enhances nuclear export of Dot1a to the cytoplasm, the resulting reduction in nuclear Dot1a expression leads to H3K79 hypomethylation and de-repression of αENaC transcription.70

Aldosterone-induced αENaC transcription includes transactivation mediated by the binding of the liganded mineralocorticoid receptor to glucocorticoid responsive elements and recruitment of Sp1 to its cis-element, and at least two epigenetic mechanisms for derepression: disruption of Dot1a-mediated histone H3K79 methylation and the targeted demethylation of the αENaC promoter (Figure 4).55

MicroRNAs and essential hypertension

microRNAs (miRNAs) are endogenously produced non-coding RNA molecules, ~22 nucleotides long, that have a ubiquitous and important role in regulating protein expression. At least 30% of human genes are thought to be regulated by miRNAs, one of the classes of small RNA.71 The human genome contains genes coding at least 2588 mature human miRNAs. Some miRNA genes are located in introns of protein-coding genes or form transcriptional unit with adjacent protein-coding genes.72 Some miRNA genes are located close to each other in the genome and form miRNA cluster.72 In addition, some miRNAs, such as miR-149 and miR-29b, are encoded by multiple copies of genes.72

Similar to mRNA, miRNAs are transcribed from endogenous miRNA genes as primary transcript (pri-miRNA), containing 65- to 70-nucleotide stem-loop structure.73, 74, 75 The hairpin structure is excised in the nucleus by the Drosha-DGCR8 complex to yield a precursor miRNA.73, 74, 75 Precursor miRNA is transported by exportin-5 into the cytosol, where Dicer cleaves the Precursor miRNA, producing a short double-stranded RNA fragment called miRNA:miRNA duplex.73, 74, 75 The duplex is successively incorporated into the RNA-induced silencing complex.10 Within the RNA-induced silencing complex the miRNA duplex is unwound and split into two single strands; the mature miRNA single strand is retained in the complex, determining the formation of miRNA-induced silencing complex, while the other strand is lost (Figure 5).10 The seed sequence of a miRNA in these protein complexes pairs with complementary sites in the 3′-untranslated region (3′UTR) of target mRNAs through RNA–RNA base pairing that involves not only the Watson–Crick A:U and G:C pairs but also the G:U pair.76 In the canonical pathway, base pairing is recognized between the 2 and 8 nucleotide seed sequence of the miRNA and the mRNA 3′UTR.77 In the non-canonical pathway, miRNA binding to its mRNA targets relies less on seed sequence homology and more on complementarity in coding regions or the 5′UTR of the target transcript.78

Figure 5
figure5

The biogenesis of miRNAs.

In general, miRNAs bind to the 3′UTR of their target mRNA and reduce the abundance of target proteins by repression of target mRNA translation and removal of mRNA poly (A) tail (that is, deadenylation), resulting in mRNA degradation.74 miRNAs emerge recently on the scene of epigenetics as factors of important mechanisms capable of modulating and controlling the expression of genes. Key miRNAs regulate the expression levels of hundreds of genes simultaneously, and many types of miRNAs regulate their targets cooperatively.79

AGT-regulated miR-584 and miR-31

Human angiotensinogen (AGT) gene, which is associated with essential hypertension in Caucasians, Japanese and Asian Indian subjects, has a C/A polymorphism at +11525 (rs7079) located in the 3′UTR.80 Both in HEK293 cells and Hep3B cells, transfection of miR-31 or miR-584 downregulates the luciferase activity of reporter construct containing only the 11525C allele and not the 11525A allele.80 Moreover, anti-miRNAs relieve the miR-584- and miR-31-induced downregulation of the luciferase gene-containing 11525C allele of the 3′UTR of hAGT gene.80 In addition, transfection of either miR-31 or miR-584 also reduces the hAGT mRNA/protein level in Hep3B cells.80 Owing to decreased binding of miR-584 and miR-31, human subjects having the 11525A allele may have increased hAGT expression compared with human subjects with the 11525C allele (Table 1).80 This may lead to increased plasma or tissue hAGT levels, ultimately resulting in increased blood pressure in human subjects with the 11525A allele compared with human subjects with the 11525C allele.80

Table 1 RAS components and target miRNAs

REN-binding miR-181a and miR-663

The transcriptome-wide study of differential expression of mRNAs and miRNAs in the kidney in human hypertension showed that several of the mRNAs identified have miRNA targets in their 3′UTR.81 Functional experiments in cultured kidney cells showed that two selected miRNA, miR-181a and miR-663, may exert posttranscriptional control of renin (REN), apolipoprotein E (APOE) and apoptosis-inducing factor mitochondrion-associated 1 (AIFM1) mRNAs via their 3′UTR.81 In human hypertension, endogenous REN gene is overexpressed and the expression of miR-181a and miR-663 is reduced.81 REN mRNA may be regulated via binding of miR-181a and miR-663 to its 3′UTR (Table 1).81

miRNA as biomarkers

miR-483-3p

miR-483-3p is one of the 22 VSMC-specific miRNAs, whose expression is decreased on chronic angiontensin I receptor activation.82 This miRNA is encoded within intron 2 of the insulin-like grow factor 2 (IGF2) gene in humans and rodents.82 IGF2 gene is known to be regulated by angiontensin II signaling and in turn IGF2 signaling affects renin–angiotensin system (RAS) functions.82

The miR-483-p targets of the components of RAS were predicted using multiple commonly used miRNA target prediction algorithms (Target-Scan, PITA, DIANA and MicroCosm). Prediction results showed that 3′UTRs of AGT, angiotensin-converting enzyme-1 (ACE-1), angiotensin-converting enzyme-2 (ACE-2) and angiontensin II receptor (AT2R) each contain a single site in the genes’ 3′UTR for miR-483-3p.82 Cotransfection experiments clearly demonstrated that miR-483-3p can effectively initiate the RNA interference process on the target 3′UTRs of AGT, ACE-1, ACE-2 and AT2R, suggesting that this miRNA could be a global regulator of tissue RAS.82 In the miR-483-3p-expressing RASMC (human aortic smooth muscle cells)–angiontensin I receptor cells, protein levels of these miR-483-3p targets consistently decrease.82 Decreased levels of AGT and ACE-1 in these cells can be rescued by transfection with an antagomir (one of miRNA inhibitors) to miR-483-3p.82 In the presence of miR-483-3p, there is no change in AGT, ACE-1, ACE-2 and AT2R transcripts.82 Thereby, miR-483-3p does not induce degradation of transcripts of these target genes, but acts on posttranscriptional levels of these genes.82 Four different RAS components could be as targets of the angiontensin I receptor -regulated miR-483-3p (Table 1).82 Thus, miRNA regulation by angiontensin II to affect cellular signaling is a novel aspect of RAS biology, which may lead to discovery of potential candidate prognostic markers and therapeutic targets.82

miR-296

hWNK4 3′UTR is highly conserved and functions as an enhancer in HEK293 and BGC823 cells, no matter whether under a heterologous or a homologous promoter.63 The enhancer and promoter of the hWNK4 gene interact physically, with the intervening DNA looped out in hWNK4-expressing HEK293 cells, but not in non-hWNK4-expressing Hela cells.63 The transcriptional factor GATA-1 and it’s motif could be a part of the bridge between the promoter and 3′UTR of hWNK4.63 After overexpressing miR-296, the level of hWNK4 protein decreases but not the mRNA. Thus, miR-296 targets on the hWNK4 3′UTR to downregulate gene expression at the posttranscriptional level.63 A coordinated modulation by miR-296 and cofactors may be attributed to hWNK4 physiopathological function and provide a novel therapeutic clue for hypertension.63

miR-9 and miR-126

A recent study in mice has revealed that the nuclear factor of activated T cells c3 and myocardia, which participate in the aldosterone-induced hypertrophic pathway, can both be targeted by miR-9.83 miR-126, which is one of the most abundant miRNAs in endothelial cells, has been found to regulate angiogenic signaling and vascular integrity.84 Based mainly on experimental animal studies, it has been suggested that miR-9 and miR-126 could have a role in human hypertension.85

To confirm their involvement in the pathophysiology of hypertension in humans, 60 patients with hypertension and 29 healthy volunteers were enrolled in this study.86 The expression levels of miR-9 and miR-126 are lower in hypertensive patients than those in healthy controls.86 miR-9 expression levels in peripheral blood mononuclear cells are positively correlated with left ventricular mass index in patients with essential hypertension.86 Administration of miR-9 mimic (double-stranded RNA oligonucleotide) could reverse the hypertrophic response induced by isoproterenol and aldosterone in cellular model.83 Examination of miR-9 and miR-126 expression levels in essential hypertensive patients in relation to 24-h ambulatory blood pressure monitoring parameters revealed significant positive correlations with the 24-h mean pulse pressure.86 These studies indicate that miR-9 and miR-126 may have the potential to be used as prognostic biomarkers and possibly as therapeutic targets in essential hypertension.86

miR-145, miR-132 and miR-212

Recent studies have also found that miR-145 is significantly more expressed in atherosclerotic plaques of hypertensive patients than in plaques from the control patients.87 A post-hoc analysis showed that treatment with angiotensin II receptor blocker is associated with higher levels of miR-145, whereas treatment with ACE inhibitors is associated with lower levels of miR-145, although these data do not show any statistical significance (P=0.06) probably due to the limited sample size (n=22).87 Plasma levels of circulating miR-132 and miR-212 are highly elevated in the heart, aortic wall and the kidney in hypertensive rats, following chronic infusion of angiotensin II,88 whereas these two miRNAs levels are significantly decreased in human arteries from bypass-operated patients treated with angiotensin II receptor blockers, suggesting that circulating miR-132 and miR-212 are involved in angiotensin II-induced hypertension and might be used for therapeutic targets during hypertension management.89

Conclusion

Epigenetic studies on hypertension should be focused, because not only there is an increasing prevalence with hypertension but also hypertension is a major modifiable risk factor for heart disease, kidney disease and stroke. Epigenetic events, differently from genetic sequence, are potentially reversible through their interface with environmental and nutritional factors. A proven effective intervention is lifestyle changes, including weight loss, reduced intake of dietary sodium, low alcohol of consumption, potassium supplementation, modification of eating habits and increased physical activity.4 Epigenetic pathways offer a new perspective in gene regulation. With further research, epigenetics might make a significant contribution for preventive and therapeutic approaches for essential hypertension.

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Acknowledgements

The study was supported by the Ministry of Science and Technology of China with ‘973’ grant 2012CB517804 and the National Natural Science Foundation of China with grants 81322002 and 81270333 to Dr Wang.

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Wang, J., Gong, L., Tan, Y. et al. Hypertensive epigenetics: from DNA methylation to microRNAs. J Hum Hypertens 29, 575–582 (2015). https://doi.org/10.1038/jhh.2014.132

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