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Arquivos Brasileiros de Cardiologia

versão impressa ISSN 0066-782X

Arq. Bras. Cardiol. vol.98 no.5 São Paulo maio 2012

http://dx.doi.org/10.1590/S0066-782X2012000500012 

REVIEW ARTICLE

 

Physical exercise and microRNAs: new frontiers in heart failure

 

 

Miguel Morita Fernandes-SilvaI, II; Vagner Oliveira CarvalhoI; Guilherme Veiga GuimarãesI; Fernando BacalI; Edimar Alcides BocchiI

IInstituto do Coração do Hospital das Clínicas de São Paulo-INCOR, São Paulo, SP
IIHospital Cardiológico Costantini, Curitiba, PR, Brasil

Correspondence

 

 


ABSTRACT

Although the impact of exercise on survival of patients with heart failure has been recently questioned, exercise training improves quality of life, functional capacity, inflammation, endothelial and autonomic function. In recent years, interest has increased regarding a group of small non-protein coding RNAs called microRNAs.
Studies have shown that the expression of these molecules changes in several pathological conditions, such as myocardial infarction, myocardial ischemia and heart failure, and when clinical improvement occurs, they seem to normalize. With the potential for practical applicability, markers that may be useful in diagnostic and prognostic assessment of heart failure have been identified, such as miR-423-5p. In addition, results of experimental studies have indicated that there are potential therapeutic effects of microRNAs.
MicroRNAs are involved in the regulation of gene expression during fetal development and in adult individuals, increasing or decreasing in the heart in response to physiological stress, injury or hemodynamic overload. Thus, the study of the behavior of these molecules in physical exercise has brought important information about the effects of this therapeutic modality and represents a new era in the understanding of heart failure.
This review aims to integrate the evidence on microRNAs in heart failure with greater relevance in the study of physical exercise.

Keywords: Exercise; microRNAs; heart rate / physiopathology.


 

 

Introduction

Several advances in the understanding of the physiopathology of heart failure (HF) allowed the development of new therapeutic modalities, or even optimized them, with a consequent increase in survival. Nevertheless, HF is still a condition with high mortality and morbidity, being the leading cause of hospitalization due to cardiovascular disease in Brazil1.

In spite of recent evidence questioning the impact of exercise on survival2, physical training improves quality of life3, functional capacity4, inflammation5, and autonomic4 and endothelial function4. The mechanisms involved in this phenomenon are not yet fully understood. In recent years, interest has increased in the area of research involving aspects related to the body's response to exercise in the genetic scenario, in which microRNAs appear to play a key role.

It has become increasingly evident that microRNAs play a critical role in many biological processes, and research in cancer and cardiovascular diseases have been the main focus in translational medicine. Recent studies have evaluated the expression of several microRNAs in myocardial hypertrophy, myocardial infarction and heart failure, which will improve the understanding of the physiopathology of these clinical conditions, in addition to their promising use in the diagnosis and prognosis of major cardiovascular diseases6,7. Moreover, the possibility of mimicking microRNAs with reduced expression or antagonizing those of which increased expression would be causally linked to a specific pathology, represent a therapeutic potential and new paradigm in the management of heart diseases.

Implicated in the regulation of gene expression during fetal development and in adult individuals8,9, many of these microRNAs increase or decrease in the heart in response to physiological stress, injury or hemodynamic overload10. The study of the behavior of these molecules in physical exercise therefore represents a great potential for new discoveries of this type of therapeutic modality in HF.

This review aims to integrate the evidence for microRNAs in heart failure with greater relevance in the study of physical exercise.

MicroRNAs

In response to external stimuli such as exercise, gene expression can be modulated by different mechanisms, including gene silencing by small RNAs, including the microRNAs (miRNAs)11.

The miRNAs, initially described in 1993 when studying the development of nematodes12, are characterized as a group of small non-protein-coding RNAs, with approximately 19-25 nucleotides in length. Unlike the wide range of RNAs encoded by the human genome, this variety of RNA has been noted for its unique ability to modulate an enormous and complex regulatory network of gene expression13.

It is currently known that, in general, miRNAs are synthesized from specific genes or certain genetic regions that are not associated with protein production (introns)11. The maturation process of miRNAs involves a complex metabolic pathway that begins in the nucleus and extends to the cell cytoplasm (Fig. 1). The first step in the miRNA maturation is the transcription of a long primary miRNA strand (pri-miRNA) from a certain gene14. The pri-miRNA is cleaved by an enzyme complex called Drosha, releasing precursor regions called pre-miRNAs, which will form distinct miRNAs15. In the cytoplasm, after being exported from the nucleus by exportin-516, the pre-miRNA is cleaved by the Dicer enzyme, forming a double-stranded RNA with approximately 22 nucleotides17. The two strands are then separated; however, only one of them will potentially act as a functional miRNA, while the other is generally degraded18.

In its mature form, miRNAs, with the help of an enzyme complex called RNA-Induced Silencing Complex (RISC), binds to the target messenger RNA (mRNA). This binding prevents the ribosomes from accessing the genetic information contained in the mRNA, resulting in decreased protein synthesis of the target gene19,20.

In general, the function of miRNAs is to act as a recognition component for RISC, as they bind to mRNA, identifying it as a target. The complexity of protein expression regulation by miRNA is illustrated by the fact that a single miRNA can regulate hundreds of distinct target genes, and otherwise cooperate to control a single target gene 2,13.

More than 700 human miRNAs have been identified and there seems to be 150 to 200 of them expressed in the heart10. This number is expected to grow even further, due to the recent development of sequencing technologies and computational prediction methods19,20. Although the biological functions of miRNAs are not fully understood, it is believed that 30% to 60% of the protein-coding genes are regulated by miRNAs11.

Studies have shown that although miRNAs are expressed in various cell types, specific miRNAs are synthesized exclusively in certain tissues or cell groups19,20.

MicroRNAs and heart failure

In recent years, it has been shown that many miRNAs are expressed in a specific way in some cardiovascular conditions. Specifically, there is a differential expression in hypertrophy, myocardial ischemia and endothelial dysfunction.

Systolic HF is characterized by ventricular dilatation and remodeling and there seems to be an activation of a fetal gene program that triggers pathological changes in the myocardium, associated with progressive ventricular dysfunction21. A pattern of miRNA expression very similar to that found in fetal hearts has been identified in the heart of patients with advanced-stage HF21. Moreover, in a study evaluating22 patients with dilated, ischemic and valvular cardiomyopathy (aortic stenosis), the expression profile was different according to the etiology of HF, and the miRNA signature was able to predict diagnosis with an accuracy of 70%.

Four families of miRNAs are highly expressed in the heart: miR-1, miR-133, miR-208 and miR-499. The miR-1 family represents 40% of all miRNAs expressed in the heart, whereas the miR-208 is the only one known as cardio-specific. Table 1 contains some miRNAs and their possible biological effects on the adult heart.

 

 

The miR-1 is reduced in myocardial hypertrophy, and in vitro23 and in vivo24 studies indicate that there is a causal relationship, in which the reduction of this miRNA is a necessary condition for cell mass increasing25. An experiment in rats26 showed that one of the earliest changes observed after pressure overload to the heart is the reduction in miR-1, even before the increase in cardiac mass. The miR-1 is reduced in the hypertrophic ventricle of patients with acromegaly26 and aortic stenosis22 with preserved ejection fraction.

On the other hand, the expression of miR-1 shows different findings in HF. While some authors22,27,28 observed a reduction in miR-1 in ischemic and non-ischemic dilated cardiomyopathy, others observed an increase21,29. Han et al25 suggest the possibility that miR-1 is reduced in hypertrophy, but returns to normal or above normal when the condition progresses to HF.

The family of miR-208 is restricted to the heart and consists of the miRs-208a and -208b, which are encoded in introns of genes of myosin heavy chains (MHC) α and β, respectively30,31. The interactions of these miRNAs with the MHC genes are involved in the development of hypertrophy in adults.

Other miRNAs also show a differentiated expression in hypertrophy and myocardial ischemia. Some examples are shown in Table 2.

 

 

Changing in miRNA expression in response to heart functional alterations have also been demonstrated. An interesting study29 evaluated the profiles of mRNA and miRNA in 10 hearts treated with left ventricular assistance device (LVAD), 17 hearts of individuals with HF not treated with LVAD and 11 controls (no HF). In the hearts of individuals with HF without LVAD, a significant increase in the expression of 28 miRNAs was observed, while in those treated with LVAD, 20 of these miRNAs were completely normalized, and the other eight tended to normalization. Experimental studies32 have shown that a phenotype can be reversed through the inhibition of a specific miRNA that has an increased expression in this condition. This can be accomplished by administering an anti-miRNA oligonucleotide, which acts as a competitive inhibitor of that miRNA and is called antagomiR. Recently, Montgomery et al33 demonstrated that administration of an anti-miR-208a antagomiR was able to prevent ventricular hypertrophy, cardiac remodeling and mortality in Dahl rats due to HF (sensitive to salt) subjected to a hypersodic diet.

The study strongly suggests that the effects of antagomiR were due to reduced levels of miR-208a. This result not only establishes a causal correlation of this miRNA with the mechanism of hypertrophy, but also brings a very promising therapeutic use to reverse remodeling. However, in adult rats, the profile miR-208a/α-MHC is predominant, and when pressure overload occurs, there is a shift in the production from α to β-MHC30,31. In humans, the role of this mechanism in hypertrophy remains to be clarified, as this species is not able to reverse the MHC isoforms, and the β-MHC is the predominant form, together with the miR-208b31. In addition, experimental models must be viewed with caution when extrapolating data, as they are artificial and may not accurately mimic the clinical conditions observed in humans10.

MicroRNA as biomarker in heart failure

For a widespread use of miRNA as a biomarker in heart failure, its determination must be simple and reliable, preferably dispensing with the need to perform an invasive procedure such as a biopsy. Although the research of miRNAs in tissues and cells have been carried out for some time, only recently it was found the existence of a series of these miRNAs in circulating blood. Mitchell et al34 demonstrated in patients with prostate cancer that tissue-specific circulating miRNAs could be detected in plasma. The mechanisms by which they are released are uncertain, but it has been postulated to be through the secretion within microvesicles called exosomes35. It is unknown whether this occurs with other miRNAs, but characteristics such as specificity and stability in plasma make it very promising as a marker of tissue injury36.

The miRs-208a, -208b and -499 miRNAs are specific to cardiomyocytes and were evaluated in the diagnosis of conditions that cause myocardial injury. There was an increase of more than 1,000-fold in acute myocardial infarction6,37-39 of miRs-208b and-499. In this condition, they reflect tissue injury and cell death. In addition, miR-208a showed diagnostic accuracy that was similar to troponin, with the advantage of being detected earlier in plasma6.

In order to determine which could be used as biomarkers in HF, Tijsen et al40 compared the expression profile of miRNAs in the plasma of 12 healthy subjects with 12 patients admitted for acute HF. Among 108 miRNAs that showed significant difference between the groups, 16 were selected and validated in a larger group, including 30 patients with HF, 20 who had dyspnea due to other causes rather than the HF, and a third group of 39 healthy individuals. In this validation cohort, an elevated level of mir-423-5p was strongly associated with the diagnosis of HF in a logistic regression model including age and sex. The mechanisms by which there is an increase in this marker in patients with HF remains unknown. Whether this is due to cell damage and subsequent release of that in plasma, or is related to a specific secretory pathway of a given cell, it remains to be clarified41. In another study7, plasma concentrations of miR-126 showed an inverse correlation with the levels of brain natriuretic peptide (BNP). However, the patient sample was heterogeneous and the criteria for HF were not well established. More studies are needed to define the role of these miRNAs as biomarkers in HF.

MicroRNA and exercise

Physical exercise, pregnancy and the individual's growth are stimuli for physiological increase of the heart. In the mid-nineteenth century, descriptions of the so-called "athlete's heart" had deleterious connotations8. More recently, the multiple benefits of physical training on survival and the harmful effects of a sedentary lifestyle made this therapeutic modality required to treat patients with heart disease, including those with systolic ventricular dysfunction, who have already shown a pathological increasing in ventricular volumes and masses. Its benefits regarding functional capacity can be explained by effects on endothelial function, peripheral vascular resistance and changes in the structure of skeletal muscle, although significant improvement in left ventricular ejection fraction have not been demonstrated.

The study of microRNAs may generate hypotheses about the mechanisms by which exercise affects the pathophysiology of HF. Interestingly, the signaling pathways leading to hypertrophy due to physiological stimuli such as exercise, are different from those that cause pathological hypertrophy and thus may trigger different expressions in miRNAs8. Ischemic preconditioning and its relationship with the miRNA is already being evaluated in experimental studies42.

When analyzing individual responses to physical training, doubts are raised concerning the reasons for the variability of their results. There is evidence that physiological adaptability to exercise has a parallel with gene expression43. However, the complexity of the genetic interaction limits the identification of individual genes that may explain this variability44. Moreover, its expression changes according to the stimulus that the body receives and it is in this aspect that the study of miRNAs has a promising role.

The skeletal muscle is also an organ with high plasticity, capable of altering the phenotype in response to mechanical overload45. Experimental studies have identified changes in the skeletal muscle profile of specific miRNAs in aerobic and resistance exercises46 (Table 3).

There are several miRNAs present in skeletal muscle, and miRs-1, -133a, -133b and -206 comprise 25% of them, often being referred to as "myomirs"47. In healthy subjects, these four myomirs decrease significantly after 12 weeks of aerobic training48, indicating that they adjust quickly to the level of physical activity. Interestingly, these levels return to baseline after 14 days of its discontinuation. When evaluating their response to a single exercise session, an increased expression of miR-1 and 133a was observed only before the training period.

With respect to resistance exercise, the gain in muscle mass is also highly variable among individuals. This variability is also accompanied by differences in the behavior of miRNAs. A study47 that analyzed biopsies of the vastus lateralis muscle of 56 men undergoing resistance training for 12 weeks found that the expression of miR-378 decreased and that of miR-478 increased, both significantly, only in those who responded little to the training. In addition, there was a strong correlation between the variation in the expression of miR-378 with the gain in lean body mass. With respect to myomirs, resistance exercise did not change miRs-1 and -133 in this study.

With respect to the levels of miRNAs in circulating blood, Baggish et al49 studied the behavior of miRNAs that were previously implicated in angiogenesis (miR-20a, miR-210, miR-221, miR-222, miR-328), inflammation (miR-21, miR-146a), cardiac and skeletal muscle contractility (miR-21, miR-133a) and muscular adaptation to hypoxia and ischemia (miR-21, miR-146a, and miR-210). The results of this and other studies involving the behavior of miRNAs in exercise in humans are summarized in Table 4.

The study of miRNAs can also help to understand the effects of exercise on immune response, of which mechanisms remain unclear. For instance, based on the analysis of cytokines, it was observed that both pro-inflammatory and anti-inflammatory pathways are activated after strenuous exercise50. Studying the behavior of neutrophils in peripheral blood51 after a workout, it was possible to observe changes in the expression profile of miRNAs, suggesting that these contribute to changes in gene expression of immunocompetent cells52.

By the time of publication of this review, we are not aware of studies that have evaluated the behavior of miRNAs in response to physical training specifically in patients with HF.

Perspectives

Much has been discovered on the effects of exercise training on HF. In addition to improving functional capacity and survival, other evidence has shown positive results of this therapy, such as an increasing in circulating endothelial progenitor cells53, anti-inflammatory effects and effects on the endothelium, and changing in levels of interleukin-1β54, -654,55, -1056, tumor necrosis factor-α and its receptors 1 and 2 and C-reactive protein56, inducible nitric oxide synthase (iNOS)54, soluble intracellular adhesion molecule (sICAM)55, adiponectin57,58, brain natriuretic peptide (BNP)59 and others (Fig. 2). Therefore, a promising tool emerges for diagnostic and prognostic evaluation of treatment in HF, which will increase the knowledge of the effects of physical exercise in these patients, going deeper into the molecular mechanisms, with the advantage of reflecting more directly the genetic signaling pathways, linking environmental stimuli to the hereditary aspects of the individual. MicroRNAs represent a new era in knowledge of heart failure and the possible effects that exercise has on it.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

This study was funded by Fundação de Apoio à Pesquisa do Estado de São Paulo (FAPESP).

Study Association

This article is part of the thesis of doctoral submitted by Miguel Morita Fernandes da Silva, from Universidade de São Paulo.

 

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Correspondence:
Miguel Morita Fernandes da Silva
Avenida Enéas de Carvalho Aguiar, 44, Bloco I, 1° Andar - Bairro Cerqueira Cesar
CEP 05403-000, São Paulo, SP - Brazil
E-mail: miguelmorita@cardiol.br, miguelmorita@me.com

Manuscript received September 29, 2011
Revised manuscript received October 25, 2011
Accepted November 03, 2011

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