High blood pressure or hypertension is an outstanding public health problem affecting
nearly 40% of the World’s adult population. Prevalence of hypertension has a strong
socioeconomic impact and health burden. Recently, hypertension has reached epidemic
proportions, and it is estimated that ≈25% of adult individuals will be hypertensive
in the World by 2025.
1
Untreated hypertension can result in various health complications, such as stroke,
myocardial infarction, vascular disease, and chronic kidney diseases.
2
Generally, hypertension is categorized as either primary or secondary according to
its cause. However, there are several types of hypertension that are more or less
common such as essential hypertension (EHT), pulmonary hypertension (PHT), pulmonary
arterial hypertension (PAHT), white coat hypertension, and nocturnal hypertension.
This article focuses on the 3 first types for which a significant amount of information
on the role of noncoding RNAs (ncRNAs) is available. Essential, primary, or idiopathic
hypertension refers to elevated blood pressure in which secondary causes such as renovascular
disease, renal failure, pheochromocytoma, aldosteronism, or other causes of secondary
hypertension, or Mendelian forms are not present.
3
EHT is the most frequent type of hypertension, which accounts for 95% of all cases.
PHT refers to an elevation of the pulmonary arterial pressure above 25 mm Hg at rest
as assessed by right heart catheterization.
4
This elevation can be caused by different underlying diseases, such as liver disease,
thromboembolic disease, rheumatic disorders, lung conditions, including tumors, chronic
obstructive pulmonary disease, pulmonary fibrosis, or cardiovascular diseases, including
aortic valve disease, heart failure, and congenital heart disease. According to the
latest World Health Organization classification, PHT is classified depending on its
cause into 5 groups: PAHT, PHT caused by left heart disease, PHT caused by lung disease,
PHT caused by chronic blood clots, and PHT associated with other unclear conditions.
PAHT is defined as pulmonary vasculopathy and progressive pulmonary vasculature remodeling
that cause the rise of pulmonary arterial pressure.
5
Although PAHT is classified as a specific subgroup of PHT, in the literature, PHT
is often used instead of PAHT. Thus, while PHT refers to an elevation of pressure
in the lung arteries caused by a side disease, PAHT is caused by remodeling of pulmonary
blood vessels.
Owing to the fact that blood pressure is regulated by multiple physiological pathways,
it is difficult to decipher a single causative agent of hypertension. Recent studies
have shown that complex multifactorial cause of hypertension results from a dynamic
interplay of genetic and environmental factors.
6
Polygenic nature of hypertension involves many genes each with mild cumulative effects
reacting to environmental factors that contribute to hypertension. Population-based
studies have demonstrated that Mendelian forms of hypertension can be found in about
20% of families and reach 60% in twins.
7,8
Integration of data from genome-wide linkage and association studies and system genetics
approaches allowed the identification of >100 single nucleotide polymorphisms implicated
in high blood pressure.
9,10
Studies aiming to decipher the molecular pathways of high blood pressure have identified
genes involved in the renin-angiotensin-aldosterone system (RAAS), signaling through
G protein-coupled receptors, vascular inflammation, remodeling, and in the structure
and regulation of vascular senescence and developmental programming.
11
Although significant progress has been achieved in elucidating the molecular pathways
involved in the pathophysiology of hypertension, the regulatory function of these
pathways remains to be fully elucidated. Recent advances in epigenetics may provide
at least some of the missing pieces of the hereditary puzzle that can explain the
fact that a same genome can provide distinct phenotypes, without alterations in primary
DNA structure.
12
The key factor in figuring out the complex multifactorial nature of hypertension might
well hence be the dark matter of the human genome. Indeed, while it used to be commonly
accepted that each of human genes would encode proteins, it has more recently been
discovered that the majority (>95%) of these genes are unable to produce proteins.
13
These genes are transcribed into ncRNA molecules and they play multiple important
roles in regulating protein-coding genes. The ubiquitous expression of ncRNAs allows
them to regulate many physiological and pathological processes, in virtually all cell
types. Because their discovery, ncRNAs have attracted an exponential interest by the
biomedical research community, notably in the area of cardiovascular diseases and
their major risk factor, hypertension.
14
NcRNAs have been arbitrarily classified into short and long ncRNAs with a threshold
of 200 nucleotides.
15
In addition, ncRNAs have been classified according to their cellular localization
(nuclear versus cytoplasmic), mechanism of action and structure.
15,16
This review presents a comprehensive overview of the current knowledge of the role
of ncRNAs in the complex regulatory processes involved in the pathophysiology of hypertension.
We focus on microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs).
Because different ncRNAs regulate different types of hypertension, we separately review
existing data on the 3 most prevalent types of hypertension, namely EHT, PHT, and
PAHT.
Search Strategy, Data Synthesis, and Data Analysis
We searched all published studies in the PubMed database (up to March 31, 2019) using
the following combination of keywords: “noncoding RNA AND hypertension” (Figure 1A).
Furthermore, manual searches for related articles were performed to avoid missing
any relevant study. A total of 1476 records were initially identified by searching
the PubMed database. After reading the titles and abstracts, we excluded 269 articles
with inadequate data, 6 articles not written in English, 39 reviews or commentaries,
and 1046 that did not focus on ncRNAs and hypertension (Figure 1B). The remaining
116 full articles were then assessed according to following criteria: studies aimed
to investigate the relationship between ncRNAs and hypertension, clinical, animal,
in vitro and in silico studies, available data on ncRNAs expression levels, proposed
functional role, target gene, and biomarker potential. This filtering step resulted
in excluding 14 articles focused on other cardiovascular disease than hypertension,
messenger RNAs (mRNAs) or single nucleotide polymorphisms in hypertension. Finally,
102 original articles were included in the present review and were stratified according
to the type of hypertension (Figure 1B). The following information was extracted from
each article: first author, year of publication, type of ncRNAs, method of detection,
species, type of samples, expression of ncRNAs in hypertension, ncRNA’s target gene
and method of target gene detection, and proposed role of ncRNAs in hypertension.
Figure 1.
Literature search. A, Flow chart methodology used for data extraction (original articles).
PubMed search was performed using the keywords “noncoding RNA AND hypertension.” B,
Distribution of evaluated and included original articles according to type of hypertension.
CVD indicates cardiovascular disease; EHT, essential hypertension; mRNA, messenger
RNA; ncRNA, noncoding RNA; NHT, nocturnal hypertension; OA, original articles; PAHT,
pulmonary arterial hypertension; PHT, pulmonary hypertension; SNPs, single nucleotide
polymorphisms; and WCHT, white coat hypertension.
MiRNAs and Hypertension
MiRNAs are short endogenous conserved ncRNAs with important roles in regulating gene
expression programs that underlie normal and pathological cellular processes, including
cardiovascular diseases.
17
Individual miRNAs have the capacity to simultaneously regulate a large number of genes
through their coordinated activities on different pathways and networks. Increasing
data have revealed that abnormal miRNAs expression and function can be related to
pathogenesis or target organ damages of hypertension. MiRNAs are remarkably stable
and are present in circulating cells or exosomes found in body fluids, such as blood,
serum, and urine.
14
Because of miRNAs presence in body fluids and their altered expression levels in elevated
blood pressure, they have drawn attention as potential biomarkers for different types
of hypertension.
MiRNAs in EHT
The expression profiles, target genes, and proposed functional roles of miRNAs shown
to be associated with EHT are shown in Table 1. Regulation of miRNA expression levels
was obtained either by comparing patients with hypertension and healthy individuals,
or in animal models of hypertension, or in cultured cells. This heterogeneity accounts
for some of the variability between reports. Owing to the fact that miRNAs and their
target genes are involved in a complex molecular network of vascular metabolism, they
may affect EHT development in several ways.
Table 1.
MicroRNAs Associated With EHT
The RAAS represents a well-tuned network of peptides, substrates, enzymes, hormones,
and receptors that act together to regulate blood pressure. Multiple miRNAs interact
with the RAAS system. Downregulated miR-34b, miR-361-5p, miR-362-5p, and miR-181a,
acting via their target genes, may alter homeostasis of the RAAS.
18–20
MiR-29b alters Sp1-TGF (transforming growth factor)-β/Smad-nuclear factor-kappa B
signaling pathways in human and rats.
21
Furthermore, upregulation of miR-34c-5p, miR-449b, miR-571, miR-765, miR-483-3p, miR-143/145,
miR-21, miR-126, miR-196a, miR-132, miR-212, and miR-451 may induce an imbalance in
RAAS system resulting in elevated blood pressure.
45
MiR-663 can regulate REN (renin) and APOE (apolipoprotein E) mRNA levels via binding
to REN and APOE 3′ untranslated regions whereas miR-181a regulates REN and AIFM1 (apoptosis-inducing
factor mitochondria-associated 1) mRNAs.
22
Three studies reported that downregulation of miR-31a-5p,
23
miR-142-3p,
24
miR-4763-5p,
25
and miR-4717-3p
25
can induce a loss of control of cell proliferation and apoptosis in pulmonary artery
smooth muscle cell (PASMCs) and platelets in rats, while downregulated miR-4709-3p
via target gene apolipoprotein L3 gene (APOL3) induces apoptosis of human peripheral
blood mononuclear cells.
25
Cardiac hypertrophy in patients with EHT might be caused by the presence of the C
allele of rs17168525 located in the let-7/miR-98-binding site of myotrophin gene (MTPN).
26
Thus, let-7c overexpression can cause a significant decrease in the level of myotrophin
protein. Furthermore, overexpression of miR-103a-2-5p or miR-585-5p may affect oxidative
DNA damage and cell survival by regulating poly-(ADP-ribose) polymerase 1 (PARP-1)
gene expression in human aortic endothelial cells (ECs) and human umbilical vein ECs.
30
It is widely known that elevated oxygen levels may induce vascular wall remodeling
associated with endothelial dysfunction, inflammation, and cell migration. Overexpression
of miR-21 is positively correlated with elevated blood pressure in humans, and it
has been shown to directly target mitochondrial genome-encoded cytochrome b (mt-Cytb),
thereby enhancing the production of reactive oxygen species in the spontaneously hypertensive
rat model.
31
Moreover, overexpression of miR-21 can trigger the atherosclerotic process in patients
with EHT by targeting eNOS (endothelial nitric oxide synthase).
32
Upregulation of miR-135a, miR-376a, hcmv-miR-UL112, miR-296-5p, and miR-let-7e may
induce neuromodulation and catecholaminergic regulation, together with immunologic,
inflammatory, and anti-infection responses in human and rat.
33,34
In addition to hypothalamic hormone regulation of blood pressure, hypothalamic inflammation
can be a trigger of pathological events, such as oxidative stress and endothelial
dysfunction in hypertensive patients.
ECs play a crucial role in the development, maintenance, and remodeling of vascular
network.
46
Dysfunctional vascular endothelium leads to impaired vasodilatation and a proinflammatory
and prothrombic phenotype of the vessel wall.
47
MiRNAs play significant roles in the vascular wall and their deregulation may alter
the function of ECs. MiR-505 and miR-126 are necessary for angiogenesis and endothelial
migration.
35,46
MiR-130a and miR-487b regulate the proliferation of vascular smooth muscle cells (VSMCs)
and medial smooth muscle cells via downregulation of GAX (growth arrest homeobox transcription
factor)
36
and IRS1 (insulin receptor substrate 1)
37
expression, which may contribute to vascular remodeling in vascular disorders such
as EHT. Finally, many of the miRNAs listed in Table 1 have been shown to be downregulated
or upregulated in hypertensive subjects or in animal models,
27–29,38–44
although their role in the development and progression of EHT remains to be elucidated.
MiRNAs in PHT
MiRNAs have an important role in the maintenance of pulmonary vascular homeostasis
and in the pathogenesis of PHT
48
(Table 2). MiR-let-7b might be involved in the pathogenesis of chronic thromboembolic
PHT by affecting ET-1 (endothelin-1) expression and the migration of pulmonary artery
ECs and PASMCs.
49
Downregulation of miR-208 was observed during the progression towards right ventricular
failure and its inhibition activates the complex mediator of transcription 13/nuclear
receptor corepressor 1 axis, which, in turn, promotes Mef2 inhibition.
50
By targeting androgen receptor and protein kinase C-α, miR-3148, which is downregulated
in chronic thromboembolic PHT, might play a role in the development of chronic thromboembolic
PHT.
51
In female mice carrying a heterozygous mutation of the bone morphogenetic protein
receptor II gene (BMPRII), downregulation of miR-96 was associated with a concomitant
upregulation of the 5-hydroxytryptamine 1B receptor and an increase in the proliferation
of PASMCs, which may explain the association between miR-96 and the development of
PHT in women.
52
Table 2.
MicroRNAs Associated With PHT
The ubiquitous miR-21 display upregulated expression levels in plasma samples from
humans and mice with PHT, lung, right ventricular tissues, and human pulmonary arterial
ECs.
53,54
Integration of data obtained by different approaches such as combination of in silico
predictions, cell culture data, and animal experiments, demonstrated that miR-21 acts
in Rho/Rho kinase signaling pathway as well as in pathways associated with hypoxia,
inflammation, and genetic haploinsufficiency of the BMPRII gene to control the development
of PHT.
53
MiRNA-328 regulates hypoxic PHT by targeting IGF-1R (insulin growth factor 1 receptor)
and L-type calcium channel-1C (CaV1.2), causing pulmonary vascular remodeling in human
and rats.
55
Upregulated miR-214 and miR-125a may cause proliferation of PASMCs and pulmonary ECs
in PHT.
56–58
The miR-130/301 family plays an important role in the regulation of multiple proliferation
pathways in PHT, such as apelin-miR-424/503-FGF2 signaling in smooth muscular cells,
miR-130/301 modulated STAT3-miR-204 signaling, and endothelial signaling.
59,60
Thus, these findings suggest that inhibition of miR-130/301 may prevent PHT pathogenesis.
MiRNAs in PAHT
A summary of miRNAs, their targets and proposed role associated with PAHT is presented
in Table 3. MiR-124, via targeting the splicing factor PTPB1 (polypyrimidine-tract
binding protein) and PKM1/PKM2 (pyruvate kinase M2), may cause highly proliferative,
migratory, inflammatory and metabolic abnormalities in PASMCs and fibroblasts.
64
Modification of the dysregulated miR-124, PTBP1 and PKM2 pathways may restore the
normal glycolytic flux in ECs. The association between PAHT and APLN (apelin) and
FGF (fibroblast growth factor) signaling pathways in the pulmonary vasculature is
mediated by miR-424 and miR-503.
65
MiR-125-3p, miR-148-3p, and miR-193 may contribute to PAHT pathogenesis via dysregulation
of TGF-β pathway, which plays an important role in pulmonary blood vessel angiogenesis,
macrophage infiltration, and cytokine expression in the lungs.
66
The miR-143/145 cluster is abundantly expressed in smooth muscle cells, and its promoter
responds to TGF-β by increasing the expression of mature forms of miRNAs.
67
Moreover, miR-22, miR-30, miR-let-7f,
68
and miR-140-5p
69
have been reported as important players in the dysregulation of TGF-β and BMP (bone
morphogenetic protein) signaling pathways in PAHT. Downregulation of miR-140-5p and
upregulation of TNF-α (tumor necrosis factor-α) may induce pathological events in
PAHT.
70
Table 3.
MicroRNAs Associated With PAHT
Several miRNAs are involved in the regulation of VEGFA (vascular endothelial growth
factor A) pathway. Specifically, miR-126 is enriched in ECs and its dysregulation
enhances the proangiogenic response of ECs to VEGF by repressing mRNA expression of
VEGFA suppressor SPRED-1 (Sprouty-related EVH1 domain-containing protein 1) and PI3KR2
(phosphatidylinositol 3-kinase regulatory subunit β).
71,72
In addition, loss of miR-126 diminishes MAPK (mitogen-activated protein kinase) signaling
in response to VEGFA and FGF, whereas gain of miR-126 enhances angiogenesis signaling.
73
While most miRNAs are synthesized by a canonical pathway, deep sequencing technologies
have revealed a class of miRNAs that can be generated by noncanonical biogenesis.
Interestingly, mutations in BMPRII (causing heritable PAHT) or downstream mediator
mothers against decapentaplegic homolog 9 (SMAD9) abrogated noncanonical processing
of miR-21 and miR-27a which show antiproliferative properties on human pulmonary artery
ECs and human PASMCs, providing a link between miR-21, miR-27a, and PAHT.
74
These findings emphasize the importance of the identification of heterozygous mutations
of SMAD9 gene that can effectively distinguish between the canonical and noncanonical
pathways in the pathogenesis of PAHT.
Downregulated miR-223 in human and rat lung tissue can be correlated to pathological
DNA repair, increased proliferation, and suppressed apoptosis.
75
MiR-204 and its putative targets are implicated in pathways correlated to cell proliferation
and resistance to apoptosis. Despite the fact that miR-204 might regulate several
pathways in PAH-PASMCs including Rho-associated, coiled-coil–containing protein kinase
(RhoA-ROCK), and NFAT (nuclear factor of activated T cells) pathways, aberrant expression
of miR-204 might be critical for PAHT pathogenesis.
76
However, downregulation of several miRNAs might protect against the development of
PAHT. MiR-145 was shown to be abundantly expressed in the vessel wall,
88
and mutations in BMPRII lead to upregulation of miR-145 in mice and patients with
PAHT.
68
In line with these findings, manipulation of miR-145 may represent a novel strategy
in PAHT treatment. Wnt/β-catenin signaling pathway is a key mediator of cell-cell
signaling during embryonic development, cell proliferation, cell migration, cell polarity,
neural patterning, and carcinogenesis. It is a highly conserved pathway that consists
of the canonical or Wnt/β-catenin dependent pathway and the noncanonical or β-catenin–independent
pathway. Interestingly, the Wnt/β-catenin signaling pathway is one of the critical
pathways in PAHT pathogenesis. Aberrantly expressed miR-let-7a-5p, miR-26b-5p, miR-27b-3p,
miR-199a-3p, miR-656,
78
and miR-199a-3p
79
strongly correlate to major PAHT-related pathways, including Wnt/β-catenin signaling
pathway. Moreover, upregulated miR-27b targets NOTCH1 (notch receptor 1)
80
and PPAR-γ (peroxisome proliferator-activated receptor γ)
81
in the NOTCH, Hsp90-eNOS, and nitric oxide signaling pathways respectively, leading
to progression of PAHT.
A common feature of miRNAs is their pleiotropic effects because of regulation of several
target genes and thereby several biological pathways. As an example, miR-23a has shown
a pleiotropic effect on the function of several PAHT-related genes including PGC1-α
(PPAR-γ coactivator 1-α), CYTC (cytochrome C), SOD (superoxide dismutase), NRF2 (nuclear
factor 2), and HO1 (heme oxygenase 1).
82
Right ventricular hypertrophy and lung vascular remodeling are strongly correlated
with PAHT. Reduced miR-322-5p contributes to the PAH-related right ventricular hypertrophy
by increasing the expression of IGF-1 (insulin-like growth factor 1).
83
Overexpression of miR-130a in lung microvascular ECs is critical in lung vascular
remodeling, an effect involving its target gene BMPRII.
84
Multiple other miRNAs have been shown to be aberrantly expressed, and their role in
the pathogenesis of PAHT needs to be further explored.
77,85–87
Common miRNAs in EHT, PHT, and PAHT Pathogenesis
Integration of published data revealed that multiple miRNAs are associated with the
pathogenesis of different types of hypertension (Figure 2). This was expected considering
their pleiotropic properties, their ability to regulate the expression of numerous
target genes, and their involvement in complex regulatory networks. However, only
2 miRNAs, miR-21 and miR-130a, were found to be upregulated in EHT, PHT, and PAHT.
MiR-21 is highly expressed and its role in VSMC proliferation and apoptosis, cardiac
cell growth and death, cardiac fibroblast functions, and hypertension has been extensively
reported.
89
Blood pressure-related changes in circulating concentrations of miR-21 may play a
role in the increased risk of vascular disease and associated events in adults with
hypertension.
90
The dysregulation of miR-21 expression induced by the hypobaric hypoxia closely correlates
to decreased arterial blood oxygen content parameters in healthy humans that may cause
proliferative status of PASMCs and pulmonary artery ECs in the early phase of hypoxic
exposure.
91
Increased levels of miR-21 and BNP (B-type natriuretic peptide) have been shown in
patients with pregnancy-induced hypertension.
92
Additionally, the elevated expression of miR-21 correlates with white coat hypertension.
93,94
Figure 2.
Venn diagram of the number of microRNAs (miRNAs) overlap between different types of
hypertension. MiRNA-21↑ and miR-130a↑ are upregulated in all types of hypertension.
MiRNA-126↓ and miR-145↑ are common for essential hypertension (EHT) and pulmonary
arterial hypertension (PAHT), while miR-204↓, miR-424↓ and miR-503↓ are downregulated
in PAHT and PHT. ↑, upregulated; ↓, downregulated.
MiRNA-130a is the most abundantly expressed member of the miR-130 family and correlates
with vascular remodeling. Recent data offer evidence that the elevated expression
levels of miR-130a may participate in the pathogenesis of different types of hypertension
through pleiotropic effects on several target genes involved in vascular remodeling.
95
However, its therapeutic potential in hypertension remains to be addressed. Additionally,
we observed that downregulated miR-126 and upregulated miR-145 are common for EHT
and PAHT, while miR-204, miR-424, and miR-503 are downregulated in PAHT and PHT. These
findings motivate future research on the role of miRNAs in the complex regulatory
networks responsible for the development of different types of hypertension.
Interaction Between Host miRNAs and the Gut Microbiota in Hypertension
In the last decade, the role of gut microbiota in the pathogenesis of hypertension
has attracted some interest. The gut microbiota consists of a plethora of different
microbes that play essential roles in the development of immune function, cell proliferation,
and metabolism, by regulating roughly 10% of the host’s transcriptome.
96
Increased population of 2 main species of microbes in the gut, Firmicutes and Bacterioidetes,
has been shown in experimental models of hypertension, including spontaneously hypertensive
rats, salt-induced models, and Ang II (angiotensin II)–induced hypertension.
97
Recent data suggest the existence of a crosstalk between host cells and microbes that
could be mediated through host miRNAs. Microbes might take up host miRNAs that are
able to affect their microbiome, while they might also produce metabolites that can
regulate the expression of host genes, including miRNAs.
98
The gut microbiota could cause endothelial dysfunction through downregulation of miR-204
expression in the vessel wall.
99
The expression of miR-21-5p could be induced by commensal microbiota, such as Helicobacter
pylori, Salmonella typhimurium, and Mycobacterium species, leading to excessive immune
responses.
100
Overall, the significance of a crosstalk between host miRNAs and the gut microbiota
in the pathophysiology of hypertension remains to be further explored.
LncRNAs and Hypertension
LncRNAs are transcripts of >200 nucleotides without known protein-coding function.
They are implicated in epigenetic processes in the nucleus, including chromatin modification,
transcription modulation, and alternative splicing regulation, while cytoplasmic lncRNAs
interact with proteins and other RNAs to modulate gene expression.
15
Despite remarkable breakthroughs of high-throughput sequencing technologies, the function
and biological significance of lncRNAs in the cardiovascular system including pathological
events related to hypertension is still limited. A few studies showed that lncRNAs
are expressed in the circulation and might be useful disease markers.
101,102
Yet, their potential biomarker value in the context of hypertension has received little
attention.
LncRNAs shown to be associated with elevated blood pressure are summarized in Table
4. The GAS5 (growth arrest-specific 5) lncRNA is widely expressed in adult tissues
and, during embryonic development, it regulates ECs and VSMCs function through β-catenin
signaling.
103
Because dysfunction of ECs and VSMCs strongly correlates to vascular remodeling, these
data suggest that GAS5 may play an important role in EHT.
103
Using a sequence-based bioinformatics method named LncDisease to predict potential
associations between lncRNAs and specific diseases, 3 lncRNAs (lnc-C16orf95–1:5, lnc-SPATA9-1:2,
lnc-SLC17A9–1:1) have been shown to be downregulated in Ang II–treated VSMCs.
104
However, this method did not predict an association between the lncRNA GAS5 and EHT,
as suggested by a previous study.
103
In a discovery phase with RNA-sequencing and a validation phase by quantitative polymerase
chain reaction, 2 lncRNAs (TCONS_00028980 and TCONS_00029009) displayed differential
expression between Dahl salt-sensitive rats and salt-insensitive, congenic Brown Norway
SS.13 rats exposed to a high-salt diet, suggesting a role for these 2 lncRNAs in hypertension.
105
Results from a genetic study in human support a role for polymorphisms rs10757274,
rs2383207, rs10757278, and rs1333049 within the lncRNA CDKN2B-AS1 in increasing the
susceptibility to develop EHT.
106
A microarray analysis of ipsilateral renal cortex tissue revealed 145 differentially
expressed lncRNAs between spontaneously hypertensive rats and normotensive Wistar-Kyoto
rats, thus further supporting that lncRNAs might be involved in the pathogenesis of
hypertension.
107
Additionally, the 4 lncRNAs TCONS_00052110, TCONS_00201718, TCONS_00094247, and TCONS_00296056
were upregulated in failing right ventricles of Sprague-Dawley rats treated with monocrotaline
to establish PAHT and lipopolysaccharide to induce acute inflammation and heart failure.
5
A lncRNA termed MANTIS was downregulated in patients with PAHT, as well as in rats
after administration of monocrotaline, and played a role in the angiogenic function
of ECs.
108
Inhibition of MANTIS through CRISPR/Cas9-mediated gene editing, small interfering
RNAs, or GapmeRs had favorable effects on ECs subjected to shear stress, suggesting
that this lncRNA, which is also altered in patients with PAHT, might constitute an
interesting therapeutic option for hypertension.
108
A lncRNA called Giver (growth factor- and proinflammatory cytokine-induced vascular
cell-expressed RNA) is involved in Ang II–mediated VSMC dysfunction, is upregulated
in arteries from hypertensive patients and downregulated after treatment with angiotensin-converting
enzyme inhibitors and angiotensin receptor blockers, observations that support its
potential as antihypertensive drug.
109
The lncRNA H19 was upregulated in serum and lung samples from rats and mice after
monocrotaline treatment, and this was associated with PASMCs proliferation.
110
Knocking-down H19 had protective effects on pulmonary artery remodeling and PAHT development
in mice treated with monocrotaline.
110
The lncRNA-AK098656 was upregulated in the plasma of patients with hypertension and
promoted VSMC proliferation.
111
LncRNA-AK098656 transgenic rats developed spontaneous hypertension with narrowed resistant
arteries.
111
Depletion of LnRPT (lncRNA regulated by platelet-derived growth factor and TGF-β)
promoted PASMCs proliferation and this lncRNA was downregulated in pulmonary arteries
from rats after monocrotaline-induced PAHT, consistent with a role in the development
of PAHT.
112
LncRNA MRAK048635_P1 was weakly expressed in spontaneously hypertensive rats and its
downregulation in VSMC stimulated the proliferation and migration of VSMCs, concomitantly
with a phenotypic switch from a contractile to a secretory phenotype, key features
of EHT.
113
Two lncRNAs, UCA1 and Hoxaas3, participated in the induction of proliferation of PASMCs
on hypoxic stress.
114,115
Together, these preclinical studies support a role for lncRNAs in the development
of hypertension and the potential for drugs targeting lncRNAs to treat hypertension.
Table 4.
Long and Circular Noncoding RNAs Associated With Hypertension
CircRNAs and Hypertension
CircRNAs are lncRNAs characterized by their structure and highly evolutionary conservation.
Unlike linear lncRNAs, circRNAs have a covalently closed loop structure generated
during a back-splicing event between 2 or more exons.
120,121
This loop structure protects circRNAs from degradation by exonucleases and thereby
confers them with a high stability, in opposite to linear lncRNAs which are relatively
unstable because of digestion by exonucleases. Although circRNAs are still looking
for a place in the complex regulatory network of gene expression, they have been reported
to orchestrate gene expression either by acting as miRNA sponges or through interactions
with RNA binding proteins.
122
Recently, circRNAs have gained attention in cardiovascular pathology, because of their
tissue-specificity and their presence in the circulation, which makes them potential
disease markers.
123,124
However, their role in hypertension is still poorly characterized.
The latest findings of the role of circRNAs in hypertension are summarized in Table
4. The hsa_circ_0037911 has been suggested to play a role in the development of EHT
because of significantly increased expression in patients with hypertension.
116
The 4 circRNAs hsa-circ-0000437, hsa-circ-0008139, hsa-circ-0040809, and hsa-circ-0005870
seem to be dysregulated in plasma samples obtained from patients with EHT.
117
Hsa_circ_0014243 is upregulated in whole blood of patients with EHT.
118
The rat circRNA rno_circRNA_006016 may play a role in the regulatory network of blood
pressure through circRNA-miRNA-gene interaction in different signaling pathways such
as the small GTPase-mediated signal transduction, ion transmembrane transport regulation
of N-methyl-D-aspartate selective glutamate receptor activity, MAPK, and Wnt signaling
pathways.
119
Hsa_circ_0002062 and hsa_circ_0022342 are associated with chronic thromboembolic PHT
development.
51
Biomarker Potential of ncRNAs in Hypertension
Several properties of ncRNAs suggest their potential value as biomarkers of hypertension:
they are present and stable in the circulation, they are measurable using reliable
and sensitive techniques, their expression is dynamic and changes on disease status,
and they participate in disease evolution.
Among ncRNAs, miRNAs have been mostly investigated and their diagnostic potential
for different types of hypertension has been suggested. Reports (61–64) have shown
that miR-206, miR-451, miR-1246, miR-23b, miR-130a, miR-191, miR-451, and miR-26a
are dysregulated in human blood samples. Several miRNAs, such as miR-199a-3p, miR-208a-3p,
122-5p, and 223-3p have shown good diagnostic performance for hypertension.
125
Dysregulation of those miRNAs may impact risk of EHT. Downregulated (miR-451 and miR-1246)
and upregulated (miR-23b, miR-130a, and miR-191) may be considered as potential biomarker
for early detection of PHT.
62
Combination of expression levels of plasma miR-451 with echocardiography may serve
as a diagnostic reference for PHT.
63
Enhanced expression of circulating miR-19a in PAHT suggests that it may be proposed
as novel biomarker for the diagnosis of PAHT.
85
A muscle-specific miRNA, miR-206 regulates the growth of cardiac myocytes and PASMCs.
Combination of dysregulated miR-206 expression, cardiac remodeling, and neuroendocrine
biomarkers may be helpful for the screening and identification of PHT.
61
The diagnostic or prognostic value of lncRNAs and circRNAs for hypertension has been
so far poorly addressed. Differentially expressed lncRNAs: NR_027032, NR_034083, and
NR_104181 in patients with hypertension and healthy individuals, support their roles
in the pathogenesis of EHT.
126
The circRNAs hsa_circ_0014243 may find utility as a diagnostic biomarker of EHT.
118
Additionally, the combination of hsa_circ_0037911 and hsa-miR-637 may serve as significant
biomarker for early diagnosis of EHT.
127
Therapeutic Potential of ncRNAs in Hypertension
Despite continuous progress in the development of antihypertensive drugs, an epidemic
proportion of hypertension worldwide pinpoints necessity for identification of novel
and vigorous antihypertensive therapy. Multiple advantages of miRNAs, such as small
size, evolutionary conservation among species, and their known sequence, are promising
features for tailoring new therapeutic strategies for different diseases, including
hypertension. Restoring altered miRNAs expression in hypertension can be achieved
by introducing miRNA mimetics (miRNA-mimic) or anti-miRNA oligonucleotide inhibitors
known as antagomiRs. Recent evidence has demonstrated the antihypertensive effect
of recombinant adeno-associated virus-mediated delivery of miR-21-3p in hypertensive
rats via miR-21-3p-mediated positive modulation of mt-Cytb translation in mitochondria.
128
AntagomiR-155 markedly decreased systolic and diastolic blood pressures, jointly with
an elevation of the cell cycle regulator p27 (a direct target of miR-155) and α-smooth
muscle actin expression in thoracic aortic media and a reduction of the thickness
of tunica media in a rat model of hypertension.
129
Therapeutic inhibition of cardiac-specific miR-208a by subcutaneous delivery of miR-208a
antisense prevents pathological cardiac remodeling during hypertension-induced heart
failure in rats.
130
In experimental models of PAHT induced by hypoxia or monocrotaline in rodents, injection
of antagomiRs against miR-17 improved cardiac and pulmonary function through interference
with pulmonary and right ventricular vascular remodeling.
131
AntagomiR-20a prevented the development of vascular remodeling, in parallel with a
restoration of functional levels of BMPRII, in a hypoxia-induced mouse model of PHT.
132
Although miRNAs have demonstrated some therapeutic potential in preclinical studies,
the implementation of miRNAs antihypertension therapy in patients should be considered
with caution due notably to their pleiotropic nature associated with multiple cellular
pathways in different cell types and tissues. Modulation of a miRNA could be beneficial
in a particular cell type or tissue but may also induce detrimental side effects.
To date, whether targeting lncRNAs and circRNAs may help to treat hypertension remains
an open question.
Conclusions and Future Directions
The available data summarized in this review article provide evidence that ncRNAs
control numerous genes and biological processes, as well as navigate different signaling
pathways involved in the regulatory network of hypertension. Furthermore, a dysregulation
of ncRNAs expression can trigger cellular dysfunction and promote the development
of pathological events related to hypertension. Owing to a certain tissue-specificity,
ncRNAs might be considered as a novel class of antihypertensive drugs. AntagomiRs
against miR-20a and miR-155 showed interesting protective effects in rodent models
of hypertension. MiR-21 and miR-130a seem to be commonly regulated in EHT, PHT, and
PAHT, while most miRNAs show distinct profiles of regulation between different types
of hypertension, consistently with different features of each type of hypertension.
It is tempting to speculate that miRNAs might be used both as diagnostic markers and
therapeutic targets and thereby have the capacity to move the Theranostics field a
step forward.
The present review shows that only a fraction of hypertension-related lncRNAs and
circRNAs have been discovered and studied. Only a couple of lncRNAs have been tested
for their ability to prevent or treat hypertension. No circRNAs have, so far, been
engaged in such studies. The biomarker potential of lncRNAs and circRNAs as well has
been poorly addressed. As a matter of fact, there is a substantial gap in knowledge
of diagnostic and therapeutic potential for hypertension between miRNAs and other
types of lncRNAs or circRNAs. Although significant progress has been made in the technologies
used for the discovery and validation of novel ncRNAs, their clinical applicability
(both as biomarker and therapeutic target) still needs to be demonstrated. Suitable
delivery methods shall be implemented and the side effects and toxicity of modulating
gene expression needs to be carefully examined. Properly sized and properly designed
patient cohorts shall be engaged into biomarker studies. Use of extensively validated
and homogenized experimental protocols is paramount to generate robust and reproducible
results translatable into high-impact outcomes for public health. Finally, whether
ncRNAs have the capacity to aid in advancing personalized healthcare is still an open
question.
Sources of Funding
This work is supported by COST (European Cooperation in Science and Technology) Action
EU-CardioRNA CA17129. Y. Devaux is funded by the National Research Fund (grants nos.
C14/BM/8225223 and C17/BM/11613033), the Ministry of Higher Education and Research,
and the Society for Research on Cardiovascular Diseases of Luxembourg.
Disclosures
None.