The Regulation of Pyroptosis and Ferroptosis by
MicroRNAs in Cardiovascular Diseases
Akram Shariati1, Venus Shahabi Raberi2, Mehdi Masumi2, Ali Tarbiat2, Elham Rastgoo3, Reza Faramarz Zadeh2
1 Department of Cardiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
2 Seyed-Al-Shohada Cardiology Hospital, Urmia University of Medical Sciences, Urmia, Iran
3 Department of Radiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
GMJ.2023;12:e2933
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Correspondence to:
Reza Faramarz Zadeh, Seyed-Al-Shohada Cardiology
Hospital, Urmia University of Medical Sciences, Urmia,
Iran.
Telephone Number: +989146048919
Email Address: Faramarzzadehreza76@gmail.com
Received 2023-02-08
Revised 2023-04-01
Accepted 2023-04-09
Abstract
Cardiovascular diseases (CVDs) are considered the most prevalent noncommunicable disease
and the leading cause of death worldwide. A plethora of evidence has revealed that microRNAs
(miRNAs) could control the inhibition or progression of CVDs by regulating pivotal cell pro-
cesses ranging from metabolism and homeostasis to programmed cell death (PCD). Pyroptosis
and ferroptosis are two major types of nonapoptotic PCDs involved in the pathogenesis of heart
failure. However, no study has discussed the crosstalk between miRNAs and these two types of
PCDs in the CVDs. The current review demonstrated that dierent types of miRNAs can regu-
late both ferroptosis and pyroptosis and thereby aect CVDs progression and inhibition. Alto-
gether, the discussed content encourages further studies to conrm that mentioned pathways are
suitable to be considered as novel therapeutic approaches against CVDs. [GMJ.2023;12:e2933]
DOI:10.31661/gmj.v12i0.2933
Keywords: Heart Failure; Cardiovascular Diseases; MiRNAs; Pyroptosis; Ferroptosis
Introduction
Cardiovascular diseases (CVDs) have been
described as one of the most substantial
health concerns and the most prevalent non-
communicable disease all around the world
[1, 2]. According to recent statistics, CVDs
are considered the leading cause of morbidi-
ty and mortality, accounting for over 30% of
all deaths worldwide [3]. More substantially,
it is well-documented that the mortality from
CVDs continues to increase; according to
2012 statistics. The reported death rate was
17.5 million which rose to about 18 million in
2016. Moreover, CVDs mortality is expected
to reach more than 22 million deaths by 2030
[4]. A plethora of evidence documented that
CVDs refer to all types of disorders associat-
ed with the cardiac tissue and blood vessels,
including cardiac arrhythmias, atrial bril-
lation, myocardial brosis, cerebrovascular
disease, peripheral vascular disease, deep
vein thrombosis, hypertension, atherosclero-
sis, pulmonary embolism, and heart diseases
such as coronary heart disease, hypertrophic
cardiomyopathy, pericarditis, dilated cardio-
myopathy, congenital heart disease, diabetic
cardiomyopathy, and rheumatic heart disease
all of which can result in a drastic condition
known as heart failure [4-6]. Heart failure is
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Shariati A, et al. Pyroptosis and Ferroptosis Regulation by Micro RNAs
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recognized as a heterogeneous syndrome with
complicated case detection [7]. The incidence
and prevalence of heart failure is increasing
worldwide due to an aging population. More-
over, heart failure is considered the most com-
mon causative factor for hospitalization in
people over the age of 65 [8].
Furthermore, it has been anticipated that ap-
proximately 8 million people over the age of
18 could suer from heart failure, and it was
estimated that approximately 40 million pa-
tients are currently aected [9]. The majority
of the human genome, about 98%, consists
of noncoding DNA, formerly known as junk
DNA. Nevertheless, the current ndings sug-
gest that almost three-quarters of the genome
potentially could be wiped out. This transcrip-
tional potential demonstrates both the signi-
cance and benets of noncoding RNAs in the
understanding, diagnosing, and treating a va-
riety of human complications [10].
In fact, noncoding RNAs are the major mod-
ulators regulating a variety of crucial cellular
processes including cellular growth, develop-
ment, dierentiation, and death, hence consid-
ered to determine cell fate. Consequently, any
impairment in their physiological transcrip-
tion is associated with serious disorders [11,
12]. Recently, a large body of evidence has
addressed the role of noncoding RNAs in the
etiology of CVDs [13]. Therefore, the current
study aimed to discuss the regulation of pro-
grammed cell death (PCD) processes includ-
ing ferroptosis and pyroptosis by microRNAs
and their role in the pathophysiology of heart
failure.
MicroRNAs (miRNAs) As the Major Regula-
tors of Vital Cell Processes
MiRNAs are a well-described class of short
noncoding RNAs (snRNAs) with 19-24 nu-
cleotides in length (average of 22 nucleotides)
recognized as the main regulators of cellular
gene expression [14]. In the early 90s, two
distinct studies from Ambros and Ruvkun
groups reported the rst miRNA, called lin-
4, in Caenorhabditis elegans [15, 16]. None-
theless, fundamental information regarding
biosynthesis, function, and mechanism was
elucidated during the following decades.
Moreover, the ongoing identication of sub-
sequent miRNAs, is still being elucidated and
novel miRNAs are being identied and de-
scribed. The majority of miRNAs are directly
transcribed by RNA polymerase II from DNA
sequences into primary miRNAs. After pro-
cessing, the primary miRNAs are turned into
precursor miRNAs and mature miRNAs [17].
Conventionally, scientists have recognized
miRNAs as negative regulators of gene ex-
pression, which are often mediated by the di-
rect interaction of miRNAs with the 3′ UTR of
target mRNAs, 5′ UTR, and coding sequences
to suppress expression via the degradation of
mRNA or silencing of the gene. However, re-
cent ndings demonstrated that these types of
snRNAs can induce overexpression of genes
under specic conditions [18]. The mentioned
less-indicated feature of miRNAs appears to
be mediated by particular interactions with
gene promoters [19].
The Mechanisms of MiRNA-mediated Regula-
tion of Gene Expression
A variety of mechanisms have been described
for miRNA-regulated gene expression, in-
cluding the intranuclear miRNA-mediated
transcriptional and posttranscriptional gene
expression [20], miRNA-mediated gene si-
lencing via the minimal miRNA-induced
silencing complex (miRISC) [21], and miR-
NA-mediated translational activation [22].
Regardless of the nature of the mechanism
by which miRNAs modify gene expression,
these snRNAs are considered crucial for ma-
jor cellular processes including cellular de-
velopment, proliferation, dierentiation, and
death. In addition, miRNAs are involved in
a plethora of pivotal biological processes.
Therefore, impaired miRNAs expression has
been attributed to various diseases.
Moreover, the secretion of miRNAs into ex-
tracellular uids, which have been extensive-
ly documented as promising biomarkers of a
variety of disorders, is another important per-
spective of the benecial function of miRNAs.
Furthermore, miRNAs appeared to contribute
to cell-cell communications as signaling mol-
ecules [23, 24].
MiRNAs Represent a Prominent Role in CVDs
The diagnostic benets of miRNAs as bio-
markers in CVDs for specic disease entities,
including myocardial infarction, coronary
Pyroptosis and Ferroptosis Regulation by Micro RNAs Shariati A, et al.
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3
artery disease, and heart failure have been
investigated in various experimental studies
and patient cohorts. The outcomes of these
attempts have put miRNAs on the verge of
implementation in clinical disease assessment
[25, 26]. Since microRNAs can aect a vari-
ety of cellular pathways, including metabol-
ic and energy homeostasis, which are highly
involved in CVDs pathogenesis, it is logical
to assume a clinical relevance between miR-
NAs and CVDs [27]. It is documented that
miRNAs are extensively involved in vascular
integrity and endothelial cell function as miR-
NAs contribute to dierent stages of plaque
progression as well as any dysregulation in
miRNAs is associated with the destabilization
and rupture of atherosclerotic plaques [28].
Moreover, several miRNAs known as angi-
omiRs, including miR-210, miR-222, miR-
126-3p, miR-221, mir-92a, and miR-132 are
responsible for the regulation of angiogenic
processes [29]. miR-126-3p is considered a
major regulator maintaining vascular integrity
and functions as a pro-angiogenic factor [30].
Furthermore, miR-126-3p is present in plate-
lets and functions as the modulator of plate-
let aggregation since its inhibition attenuates
platelet aggregation [31]. In addition, it is re-
ported that the levels of miR-1, miR-126-3p,
and miR-208 in coronary artery disease and
myocardial infarction were increased, while
the levels of miR-21, miR-133, and miR-195
were decreased [32, 33].
Similarly, several reports have attributed
heart failure to the dysregulation of miRNAs.
Heart failure at the cellular level results from
the dysfunction of cardiomyocytes and their
brosis due to excessive extracellular matrix
accumulation [34]. miR-133 is highly ex-
pressed in cardiomyocytes; however, in pa-
tients with hypertrophic cardiomyopathy, the
level of expression reduces signicantly [35].
In addition, miR-1, a part of the same cluster
as miR-133, is expressed abundantly in car-
diomyocytes, whereas lower levels are report-
ed in patients with heart failure [36].
Interestingly, either the decrease or the in-
crease in miR-1 levels has been associated
with electrophysiological abnormalities [37].
miR-208, being responsible for the regulation
of the balance between the α- and β-myosin
heavy chains, is highly abundant in cardio-
myocytes. It is documented that the modica-
tion of miR-208 is followed by better cardiac
function in patients with heart failure [34, 38].
Furthermore, the increased and repressed ex-
pression of miR-25 is reported in failing hu-
man hearts [39].
The Crosstalk between MiRNAs and PCDs in
the Incidence of Heart Failure
The role of PCDs as well as miRNAs dysreg-
ulation in CVDs, and on the other hand the
regulation of PCDs by miRNAs characterize
the crosstalk between miRNAs and PCDs in
the incidence of CVDs. Despite the wide va-
riety of cell death processes, previous studies
have divided these processes into two major
categories, including accidental cell death
programs and PCDs.
Accidental cell death programs have been de-
scribed as a passive process in that uninspect-
ed necrosis is the main type, whereas PCDs are
active processes consisting of two major sub-
types, including apoptotic and non-apoptotic
programs [40, 41]. Necroptosis, pyroptosis,
autophagy, and ferroptosis are nonapoptotic
PCDs each with distinct biochemical, mor-
phological, and functional features [42]. Since
PCDs function in important cellular processes
including the maintenance of homeostasis and
drastic events including the incidence of dis-
orders, the researchers are keen to clarify the
association of PCDs with human health prob-
lems. MiR-150, for example, can inhibit the
death of cardiomyocytes during cardiac injury
and thereby protect against heart failure [43].
The inhibition of autophagy by miR-221 is
followed by the promotion of heart failure via
modulating the p27/CDK2/mTOR axis [44].
Contradictory, the inhibition of autophagy
by miR-30 resulted in the cardioprotection
against heart failure caused by doxorubicin
[45], an extensively applied chemotherapeu-
tic agent. In addition, miR-30 and miR-132
can regulate cardiomyocyte apoptosis in heart
failure [46, 47].
Although there have been extensive studies
on the crosstalk between miRNAs and PCDs
in heart failure, the regulation of pyroptosis
and ferroptosis by miRNAs has not yet been
fully elucidated. After briey introducing
these two non-apoptotic subtypes, the present
study discusses the regulation of pyroptosis
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Shariati A, et al. Pyroptosis and Ferroptosis Regulation by Micro RNAs
and ferroptosis by miRNAs in heart failure.
A Concise Overview of Pyroptosis
Pyroptosis is recognized as an inam-
masome-induced PCD. Pyroptosis has been
reported to be mediated by specic proteins
known as gasdermins. The initial reports of
pyroptosis occurred in 1992 in myeloid cells
infected by pathogens [48]. A variety of doc-
uments have demonstrated that pyroptosis is
involved pivotally in the clearance of bacte-
rial and viral infections through two distinct
but proportionate processes [49]. Pyroptosis
is considered a critical process in physiolog-
ical cellular functions since the dysregulation
of pyroptosis is accompanied by dysfunction
in the adaptive immune defenses stimulation,
failed eciency of pathogens clearance, and
tissue damage [50]. In addition to infectious
states, it is documented that pyroptosis is acti-
vated during other disorders, including cancer
and chronic diseases [51, 52].
Previous documents have characterized py-
roptosis by the pore formation in the plasma
membrane followed by the swelling of the
cytoplasm, the rupture of the plasma mem-
brane, and nally, the entrance of the cell con-
tent into the extracellular environment [53].
The released materials include inammatory
mediators (e.g., IL-1β); thereby, pyroptosis
is believed to be associated with inamma-
tions, whether local or systemic [51]. Py-
roptosis is considered to be induced by two
distinct mechanisms, including the canonical
and non-canonical pathways. The canonical
pathway is mediated by the caspase-1 inam-
masome mechanism, and the caspase-4/5 (hu-
mans) or caspase-11 (mice) inammasome
mechanism is involved in the non-canonical
pathways [54].
A Concise Overview of Ferroptosis
Ferroptosis has been described as an iron-de-
pendent type of PCD. Two major biochemical
markers including the accumulation of iron
and lipid peroxidation, are considered the
characteristics of ferroptosis. The accumula-
tion of iron, due to its redox ability, leads to
the generation of excessive free radicals, dam-
aging DNA, and disrupting the DNA repair
system, all of which are followed by the ac-
celeration of cell senescence known as ferritin
aging [55]. Hence, the excessive accumulation
of Fe2+ has considered being an early signal
of ferroptosis, and its overload is involved in
the pathogenesis of a variety of human diseas-
es [56]. The removal of lipid electrons in the
plasma membrane by free radicals is known
as lipid peroxidation. Lipid peroxidation is
followed by the overproduction of reactive
oxygen species, oxidation of membrane poly-
unsaturated fatty acids (PUFAs), and forma-
tion of LOOH. It is documented that PUFAs
are involved in pathological processes such as
DNA damage, pro-inammatory, and the ac-
tivity of cellular enzymes as well as is known
as a cell death signal in dierent types of
PCDs, including apoptosis, autophagy, and
ferroptosis [57, 58]. Indeed, ferroptosis is me-
diated directly by damaged PUFAs [59].
The Crosstalk between MiRNAs and Pyropto-
sis and Ferroptosis in Heart Failure
Similar to those noted for the contribution of
miRNAs in the incidence of heart failure, a
variety of studies have documented the in-
volvement of pyroptosis [60, 61] and ferro-
ptosis types of PCD processes in the patho-
genesis of CVDs.
In atherosclerosis, characterized by abnormal
deposition of lipids in the aorta and obstruc-
tion of blood ow leading to coronary heart
disease and stroke, inammatory responses
and dierent types of immune cells are in-
volved [62, 63]. Hence, pyroptosis has been
shown to contribute to the formation and pro-
gression of atherosclerosis via the promotion
of the release of inammatory mediators and
the stability of the plaque [64]. In addition,
the association between pyroptosis-related in-
ammasomes and warning factors for athero-
sclerosis related to lipid metabolisms such as
cholesterol crystals and oxidized low-density
lipoprotein clarify the involvement of pyro-
ptosis in the progression of heart failure [65].
Along with that, elevated levels of inamma-
tory and lipid mediators result in the induction
of pyroptosis in vascular endothelial cells [66,
67].
The overproduction of free radicals induced
by hyperglycemia is followed by the activa-
tion of pyroptosis-related inammasomes,
alteration in lipid metabolism and energy ex-
penditure, and nally, pyroptosis in cardio-
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5
Pyroptosis and Ferroptosis Regulation by Micro RNAs Shariati A, et al.
myocytes [68, 69]. Furthermore, pyroptosis
has been demonstrated to be involved in the
cardiac broblasts and cardiac smooth muscle
cells as well as in the pathogenesis of cardiac
hypertrophy [70]. Similarly, various studies
have documented the association of ferropto-
sis with CVDs. In hypertrophic cardiomyop-
athy, for example, iron overload, along with
excessive production of free radicals and el-
evated levels of lipid peroxidation leads to
ferroptosis death of cardiomyocytes [71, 72].
In addition, alteration in the levels of factors
associated with energy homeostasis including
lactate and glucose is followed by the induc-
tion of ferroptosis in hypertrophic cardiomy-
opathy [73]. Induction of ferroptosis in dilat-
ed cardiomyopathy has been evidenced under
similar conditions as in hypertrophic cardio-
myopathy [74]. In addition, previous studies
have revealed the involvement of ferroptosis
in heart failure, suggesting this cell death pro-
cess is a promising therapeutic strategy [75,
76].
Despite extensive evidence for the involve-
ment of both miRNAs and cell death process-
es in pyroptotic and ferroptotic pathways in
heart failure, no study has addressed the pos-
sible crosstalk. Interestingly, studies assessing
the regulation of pyroptosis by miRNAs in
cardiomyocytes have been generally related
to cardiac complications caused by diabetes
and hyperglycemia. In the cardiomyocytes of
diabetic models, miR-9 could inhibit pyro-
ptotic-dependent cardiac cell loss via attenu-
ation of hyperglycemia-induced ELAVL1 up-
regulation; hence miR-9 could suppress heart
failure in diabetics through the inhibition of
pyroptosis [77].
In addition, it is documented that miR-214-3p
reduced the activity of caspase 1 and there-
by alleviated pyroptosis in high glucose-in-
duced cardiomyopathy [78]. Furthermore,
miR-141-3p suppressed high glucose-induced
pyroptosis and prevented diabetic cardio-
myopathy [78]. Concordantly, miR-133a-3p
targeted IKKε, suppressed pyroptosis, and
attenuated cardiomyocyte hypertrophy [79].
However, in high glucose-induced cardio-
myopathy, miR-30d targeted foxo3a, reduced
apoptosis recruitment domain, and increased
caspase 1 and inammatory markers leading
to pyroptosis of cardiomyocytes and heart
failure [80]. On the contrary, the studies that
have determined the crosstalk between fer-
roptosis and miRNAs have been more di-
verse. An interesting microarray data anal-
ysis demonstrated the association of various
miRNAs with genes involved in ferroptosis in
dilated cardiomyopathy and hypertrophic car-
diomyopathy [81]. Similarly, a bioinformatics
analysis reported the interaction of dierent
miRNAs, particularly miR-21-3p and miR-
1892, with ferroptosis-related genes in septic
cardiomyopathy [82].
Another bioinformatic analysis revealed that
in calcic aortic valve disease, a prevalent
state culminating in aortic stenosis and heart
failure, several miRNAs are related to key
ferroptosis genes including CYBB, HMOX1,
and HIF-1α [83].
On the other hand, the modication in the lev-
els of glutathione peroxidase 4 by miR-375-
3p resulted in the acceleration of ferroptosis,
leading to the promotion of cardiac brosis
[84]. In addition, the sponging of miR-150-5p
is associated with attenuation of ferroptosis
and activation of CCND2 all of which lead
to the alleviation of diabetic cardiomyopathy
[85]. Importantly, all the mentioned studies,
both those examining the regulation of py-
roptosis by miRNAs and those that assessed
the regulation of ferroptosis by miRNAs, rep-
resented promising ndings for the possible
consideration of these processes as a novel
therapeutic approach for CVDs. Nevertheless,
the conduct of further studies to conrm the
capability of these processes as a management
strategy for heart failure is strongly recom-
mended.
Conclusion
The ndings of the current review study re-
veal that the crosstalk between miRNAs with
both ferroptosis and pyroptosis plays a signif-
icant role whether in the inhibition or the pro-
gression of CVDs. Therefore, dependent on
the conrmation of further studies, they could
be assumed as a promising novel management
strategy for heart failure.
Conict of Interest
There are no conicts of interest to declare.
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Shariati A, et al. Pyroptosis and Ferroptosis Regulation by Micro RNAs
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