Rev Bras Fisiol Exerc 2020;19(3);250-54
COMMENT
ON ARTICLE
Commented on: Wang Lijun, MicroRNAs in heart and circulation during physical exercise
Comentário sobre: Wang Lijun, MicroRNAs no coração e na circulação durante o exercício físico
Pedro Henrique Silva
Santos1, Úrsula Paula Renó Soci2
1Fundação Estatal de
Saúde da Família/Fundação Oswaldo Cruz (FESF/FioCruz),
Salvador, Bahia, Brazil.
2Escola de Educação
Física e Esporte da Universidade de São Paulo (EEFE-USP), São Paulo, Brazil
Received
2020 May 10th; accepted 2020 June 10th
Corresponding author: Pedro Henrique Silva
Santos, Escola de Educação Física e Esporte (EEFE), Avenida Professor Mello
Morais, 65 Vila Mariana 05508-030 São Paulo SP
Pedro Henrique Silva
Santos:pedro_hss92@yahoo.com.br
Úrsula Paula Renó Soci: ursula.soci@usp.br
Wang et al. [1], recently published in the Journal of Sports and Heath
Science a review study entitled “MicroRNAs in heart and circulation during
physical exercise” in which they summarize the regulatory role of small
non-coding ribonucleic acid (RNA) molecules, the microRNAs (miRNAs), related to
physiopathology in cardiovascular disease and cardiovascular responses to
physical exercise.
MiRNAs are non-coding small sequences of RNA, 17 ~ 25 nucleotides [2],
that can regulate gene expression by partially binding in 3 'untranslated
(3'UTR) regions of the messenger RNA (mRNA) inhibiting its translation [3]. It
is known that different miRNAs can interact with a single mRNA, and an mRNA can
have its function altered by several miRNAs [4].
Thus, miRNAs, by regulating gene expression, can alter the cellular
response by altering the health-disease relationship. Wang et al. [1] by
summarizing the role of miRNAs in this process, they identify changes in
specific miRNAs in various cardiac diseases, such as cardiac fibrosis, ischemia
and reperfusion (I/R) injury, myocardial infarction and heart failure (HF), as
well as addressing the expression of miRNAs in physiological hypertrophy.
In this commented article we covered the regulation of miRNAs in cardiac
fibrosis, in I/R injury, added a topic to arterial hypertension system (SAH)
and ended with HF, evidencing the epigenetic, counter-regulatory role of these
molecules in disease and adaptation to exercise, regulating health-disease
state.
Cardiac
fibrosis
Cardiac fibrosis consists of a pathological increase in the synthesis of
extracellular matrix proteins in the heart, that induces loss of diastolic
function and later of systolic function. Cardiac fibrosis occurs in almost all
cardiovascular diseases such as myocardial infarction (MI), systemic arterial
hypertension (SAH), hypertrophic and dilated cardiomyopathy, being also a
determinant to discriminate differentiates between pathological and
physiological cardiac hypertrophy (CH) [5]. In miocardial-infarcted
mice, cardiac miRNA-29 family expression decreased after 14 days. When
miRNA-29b was inhibited, a marked increase in cardiac fibrosis and a
cardiovascular worsening were observed [6]. The authors suggested that miRNA-29
inhibition may be mediated by an increase in transforming growth factor beta (TGF-β),
which also mediates several pathological processes in the heart, including
cardiac fibrosis [7]. In contrast, aerobic exercise training increases the
expression of miRNA-29a and miRNA-29c, and is able to negatively regulate the
deposition of cardiac collagen in healthy female rats trained by swimming, with
concomitant exacerbated cardiac hypertrophy by the increase in training volume,
improved function, increased diameter of cardiac muscle cells. Thus, the
involvement of the miRNA-29 family in the regulation of physiological
hypertrophy induced by aerobic training, occurs in an opposite pattern to
cardiovascular disease [8].
Ischemia
and reperfusion injury
The ischemia and reperfusion injury (I/R) is a
condition in which the cardiac tissue presents impaired blood flow and a after
a resumption period, as coronary artery obstruction induced by myocardial
infarction. This injury occurs due to the increase in reactive oxygen species,
atherosclerosis, damaged calcium mechanism and inflammatory responses, and can
leads to necrosis of the injured cells, edema, and a non-uniform restoration of
blood flow to the damaged tissue [9,10]. In contrast, physical exercise can
improve cardiac function after I/R injury.
Liu et al. [11] reported that the increase in miRNA-222
expression can reduce the adverse effects of I/R injury in mice that swan or
performed voluntary running for 4 weeks and showed that the increase in
miRNA-222 has a protective effect against pathological cardiac remodeling. The
authors produced a transgenic animal with overexpression of miRNA-222 to assess
in vivo the effects of the expression of this miRNA on the cardiomyocyte. The
cardioprotective mechanism of miRNA-222 related to I/R goes through the
negative regulation of targets such as Homeodomain-Interacting Protein Kinases
1 and 2 (HIPK1, HIPK2), Protein binding to the homeobox telomer (HMBOX1) and
the kinase inhibitor cyclin dependent (p27). These targets are related to the
proliferative and hyperplastic phenotype of cardiac muscle cells, which shows
the cardioprotective involvement of miRNA-222 in the increase in cardiac tissue
size induced by aerobic physical training and in regenerative processes.
MiRNA-208a is regarded the strongest candidate to become a pathological
and related to physical training biomarker, due a close relationship with
cardiac contractility and metabolism, and to be exclusively expressed by heart
[12]. MiRNA-208a expression increases in the heart in patients with heart
failure and hypertensive rats [9,13,14]. Currently, this miRNA is considered as
an acute circulating biomarker of myocardial infarction, pathological
remodeling, cardiac conductance and contractility, since it increases, through
the repression of its various target mRNAs, the expression of β-type heavy
chain myosin, a pathological marker [15]. On the other hand, after high-volume
aerobic training in normotensive rats and concomitant with their physiological
adaptations, such as HC, improvement in diastolic function and increase in
oxygen consumption, there is a marked decrease in miRNA-208a expression, which
makes it special attention in the regulation between physiological and
pathological adaptive processes in the heart [16].
Systemic
Arterial Hypertension
SAH is a syndrome characterized by high blood pressure values, above
139mmHg for systolic pressure and 89mmHg for diastolic pressure [17]. In
Brazil, SAH affects more than 30% of the adult population, with prevalence
among the elderly exceeding 60% [17]. The role of regular physical exercise
stands out as a non-pharmacological measure for the treatment of SAH, since,
can act by reducing sympathetic nervous activity (ANS) [18], decreasing
capillary rarefaction, which increases the cross-sectional area of capillaries
[19]. These two physiological adaptations together contribute to the reduction
of peripheral vascular resistance, consequently, reducing blood pressure
values.
Santulli
[20] summarizes the regulation of miRNAs in essential hypertension, in a study
showing that there are changes in the circulating, urine and tissue miRNAs
(c-miRNAs), in the heart, kidney, brain and blood vessels. Neves et al.
[21] described a list of miRNAs that play a role in the pathogenesis of SAH and
that have the potential to be regulated by physical exercise, especially
miRNA-16, targeting Vascular Endothelial Growth Factor (VEGF), involved in
angiogenesis.
MiRNA-155, which targets the endothelial nitric oxide synthase (eNOS) enzyme, regulates the production of endothelial
nitric oxide (NO) involved in the process of dependent endothelial vasodilation
[21]. The consequent changes of physical exercise in the regulation of miRNA-16
and miRNA-155, demonstrate again, how exercise is crucial in the treatment of SAH,
since it promotes fundamental changes for angiogenesis, improvement of
endothelial function, through NO, in addition to, reduces vascular peripheric
ANS and vascular rarefaction.
Heart
failure
Heart failure (HF) is a clinical syndrome characterized by decreased
values of cardiac output and is the common final route of cardiovascular
diseases [22]. The regular physical exercise deserves mention among the most
effective therapies for the treatment of HF. Exercise training, in addition to
causing a change in sympathetic nerve activity, helps to improve the shortening
fraction of the cardiomyocyte and improves the cytosolic Ca++
transient, improving the activity of the regulating proteins, such as the
Sarcoplasmic Reticulum Ca++ Pump (SERCA-2a) and Phospholambam
[23].
To elucidate the exercise-induced miRNAs regulation in HF, Souza et
al. [24] traced a miRNAs profile in Wistar rats submitted to surgical
aortic stenosis and trained on a treadmill for 10 weeks. The trained rats
showed improvement in systolic and diastolic functions and reduced atrial mass
compared to untrained. The responsive miRNAs to the therapeutic effect of
exercise, with a possible cardioprotective role in HF were miRNAs-21, -132,
-155, -146b, -208b, -212, -214, studied as regulators of cardiac remodeling and
function. Recently, the study by Correa et al. [25] showed, in patients
with HF of functional classes II and III, who underwent aerobic training for 4
months, improved flow and vascular conductance, increased oxygen consumption,
and vastus lateralis skeletal muscle hypertrophy. Skeletal muscle hypertrophy
has been associated with an increase in muscle miRNA-1, which inhibits its
target, the Homologous Phosphatase and Tensin Protein
(PTEN), PTEN, in turn, inhibits the action of phosphoenositide-3 kinase,
protein kinase B and Mammalian Rapamycin Receptor Target (PI3K-AKT-mTOR), an
important protein synthesis pathway in physiological HC. Thus, physical
exercise by increasing the expression of miRNA-1 indirectly stimulates protein
synthesis. Another target of miRNA-1 is histone deacetylase 4 (HDAC-4), which,
inhibited, facilitates the transcription of deoxyribonucleic acid (DNA), which
improves muscle regeneration and atrophy in patients [25].
MiRNAs play a crucial role in the health-disease relationship and their
expression can be regulated by physical exercise. As in the article by Wang et
al. [1], the role of miRNAs in some cardiovascular diseases and how
exercise has therapeutic potential were addressed here.
In the future, new research may point to miRNAs as physiological markers
in the health-disease relationship, as well as a therapeutic target for the
control of several of these diseases.