Next Article in Journal
Variants of the Low Oxygen Sensors EGLN1 and HIF-1AN Associated with Acute Mountain Sickness
Next Article in Special Issue
Over-Expression of Copper/Zinc Superoxide Dismutase in the Median Preoptic Nucleus Attenuates Chronic Angiotensin II-Induced Hypertension in the Rat
Previous Article in Journal
Serum Calreticulin Is a Negative Biomarker in Patients with Alzheimer’s Disease
Previous Article in Special Issue
Exploring the Role of Paraoxonases in the Pathogenesis of Coronary Artery Disease: A Systematic Review
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 15
Issue 12
10.3390/ijms151221754
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Looking into a Conceptual Framework of ROS–miRNA–Atrial Fibrillation

by
Seahyoung Lee
1,2,†,
Eunhyun Choi
1,2,†,
Min-Ji Cha
1,2 and
Ki-Chul Hwang
1,2,*
1
Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 210-701, Korea
2
Catholic Kwandong University International St. Mary's Hospital, Incheon Metropolitan City 404-834, Korea
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2014, 15(12), 21754-21776; https://doi.org/10.3390/ijms151221754
Submission received: 20 October 2014 / Revised: 17 November 2014 / Accepted: 19 November 2014 / Published: 26 November 2014
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease 2015)
Browse Figure
Versions Notes

Abstract

:
Atrial fibrillation (AF) has been recognized as a major cause of cardiovascular-related morbidity and mortality. MicroRNAs (miRNAs) represent recent additions to the collection of biomolecules involved in arrhythmogenesis. Reactive oxygen species (ROS) have been independently linked to both AF and miRNA regulation. However, no attempts have been made to investigate the possibility of a framework composed of ROS–miRNA–AF that is related to arrhythmia development. Therefore, this review was designed as an attempt to offer a new approach to understanding AF pathogenesis. The aim of this review was to find and to summarize possible connections that exist among AF, miRNAs and ROS to understand the interactions among the molecular entities underlying arrhythmia development in the hopes of finding unappreciated mechanisms of AF. These findings may lead us to innovative therapies for AF, which can be a life-threatening heart condition. A systemic literature review indicated that miRNAs associated with AF might be regulated by ROS, suggesting the possibility that miRNAs translate cellular stressors, such as ROS, into AF pathogenesis. Further studies with a more appropriate experimental design to either prove or disprove the existence of an ROS–miRNA–AF framework are strongly encouraged.

1. Introduction

Arrhythmia refers to any irregular rhythm of the heart, including both rhythms that are too fast (tachycardia) and rhythms that are too slow (bradycardia). Although most arrhythmias do not cause serious problems, atrial fibrillation (AF), the most common sustained type of arrhythmia, has been recognized as a major cause of cardiovascular-related morbidity and mortality [1,2]. Over the last decade, the mechanistic understanding of AF has advanced tremendously, and microRNAs (miRNAs) have become recent additions to the collection of biomolecules involved in AF development. In fact, the notion of miRNAs acting as AF modulators is not new; reviews regarding the role of miRNAs in AF have already been published [3,4]. However, to the best of our knowledge, no attempts have been made to investigate the possible involvement of reactive oxygen species (ROS), which have been independently linked to both AF [5] and miRNA expression in cardiovascular diseases [6], in the miRNA-mediated development of AF.
Therefore, in this review, we have attempted to find and to summarize possible connections that exist among AF, miRNAs and, particularly, ROS, to understand the interactions of the molecular entities underlying arrhythmia development in the hopes of finding unappreciated mechanisms of AF. These findings may lead us to innovative therapies for AF, which can be a life-threatening heart condition. This review represents an attempt to offer a new approach to understanding AF pathogenesis and focuses on the possible interplay between ROS and miRNA rather than on AF itself. Therefore, this review will not address the mechanical details of AF (for a comprehensive review on AF, see [4,7]), nor will it address the mechanical details of miRNAs or ROS. Rather, we will briefly discuss the key characteristics of AF and related molecules, because they are most likely the primary targets of ROS-mediated miRNA regulation in AF development. Additionally, the fundamentals of both miRNA and ROS will be discussed briefly, prior to investigating the possibility of ROS-dependent regulation of the miRNAs that have been linked to AF.

2. Atrial Fibrillation (AF) and Atrial Remodeling

“Atrial remodeling” is a key term in understanding the nature of AF and is defined as any persistent changes in atrial function and structure [8]. AF may be a final result of atrial remodeling induced by various pathologic conditions of the heart [9]; however, it may also be a major cause of remodeling, which perpetuates its progression. The two fundamental components of atrial remodeling are electrical remodeling, which occurs mainly due to alterations in ion channels [10,11], and structural remodeling, which may be caused by fibrosis [12]. Additionally, Ca2+ handling abnormalities [13] and autonomic nerve activation and remodeling [14] are also factors that may contribute to atrial remodeling.

2.1. Electrical Remodeling of the Heart

The electrical remodeling of cardiomyocytes involves the modulation of ions, especially Ca2+ and K+, and intercellular ion channels (i.e., gap junctions), which participate in the electrical coupling of adjacent cells. Consequently, any ion channel, exchanger or pump, which is fundamentally a complex of proteins, may be subjected to miRNA-mediated regulation.

2.1.1. Ca2+ Regulation and Key Molecules Involved

l-Type Ca2+ currents (ICaL) are decreased during AF [15]. l-Type Ca2+ channel (LTCC)-mediated Ca2+ influx into cardiomyocytes induces the secondary release of Ca2+ stored in the sarcoplasmic reticulum (SR) via ryanodine receptor 2 (RyR2) [16]. RyR2-mediated Ca2+ leakages have been linked to AF in animal models [17]. However, the re-uptake of cytosolic Ca2+ into the SR to maintain Ca2+ homeostasis is achieved via an SR Ca2+-adenosine triphosphatase (SERCA2a), which is under the inhibitory control of the SR-associated protein, phospholamban (PLB) [18]. Another ion channel responsible for the diastolic removal of the Ca2+ released during systole is the Na+/Ca2+ exchanger (NCX). The inward current carried by this exchanger is responsible for the delayed after depolarizations (DAD) observed in patients with chronic AF [19]. Additionally, the Ca2+/calmodulin kinase type 2 (CaMKII)-dependent phosphorylation of RyR2 has been linked to the depletion of SR Ca2+ storage and increased diastolic Ca2+ levels, which illustrates its involvement in arrhythmia development [20]. As for the relationship with ROS, the activities of some Ca2+ channels are known to be modulated by ROS. For example, it has been reported that ROS inhibit LTCC current [21] and SERCA2 activity [22], while increasing the activity of NCX [23] and RYR [24]. These results indicated that ROS might play an important role in atrial electrical remodeling, which underlies AF, by significantly altering Ca2+ handling by cardiomyocytes.

2.1.2. K+ Regulation and Key Molecules Involved

K+ current plays a crucial role in the regulation of cardiomyocyte excitability; therefore, it has been implicated in AF development [25]. Encoded by the KCNJ2 gene, the Kir2.1 proteins constitute the inward rectifier K+ channels found in cardiomyocytes [26]. Cardiac inward rectifier current (IK1), along with Kir2.1 expression, is reportedly increased during AF [27,28]. Another important channel controlling inward rectifier K+ current is the acetylcholine-activated potassium channel (IKACh channel), which is composed of Kir3 subunits [29]. Activated by acetylcholine released from the vagus nerve, IKACh facilitates strong inward rectifying K+ current that mediates the parasympathetic induction of bradycardia and subsequent decreases in cardiac contractility. Its importance in AF pathogenesis has been demonstrated using knockout animals [30].
Levels of the constitutive isoform, IKAChc, are increased in AF [31]. It has been reported that shortened action potential durations (APDs) are strongly associated with AF development [32], and IKAChc is believed to be responsible for this phenomenon in tachycardia-remodeled atria, which contributes to contractile dysfunction in AF [33]. Additionally, the increased expression of small conductance Ca2+-activated K+ (SK) channels [34] and their contribution to AF maintenance by causing APD shortages have been described previously [35]. The activity of K+ channels can be modulated by ROS. For example, the Kv1.5 channel has been implicated in the development of AF [36], and blockers of the Kv1.5 channel have been investigated as therapeutic agents for AF [37,38]. According to a study examining the effects of H2O2 on this Kv1.5 channel, H2O2 treatment induced an increase in Kv1.5 current and accelerated the Kv1.5 channel [39], suggesting that such ROS-induced modulation of the K+ channel could contribute to the initiation of AF. Another example of ROS-induced modulation of the K+ channel was demonstrated in a study in which H2O2 inhibited the activity of the hERG1 K+ channel, resulting in APD prolongation [40].

2.1.3. Gap Junction Ion Channels

In the heart, the electrical coupling of adjacent cardiomyocytes is mediated by gap junction ion channels consisting of connexins (Cx), such as Cx40 and Cx43. Cx40 is located primarily in atrial tissue and the conduction system, whereas Cx43 is the most abundant connexin isoform [41]. Gap junction ion channel malfunctions have been linked to AF-induced remodeling [42,43].

2.2. Structural Remodeling of the Heart

Structural remodeling refers to progressive morphological and functional alterations of atrial substrates, particularly the posterior wall of the left atrium. Various diseases and aging can induce these changes [44,45]. Hallmarks of structural remodeling include atrial dilation and progressive interstitial fibrosis. For example, heart failure-induced prominent ultra-structural changes include cardiomyocyte hypertrophy and extensive interstitial fibrosis [46]. Fibrosis may disrupt myocardial electrical continuity by interfering with inter-myocyte coupling, promoting AF [12,47]. Known mediators that promote fibrosis include angiotensin II (AngII) [48], transforming growth factor beta 1 (TGF-β1) [49] and platelet-derived growth factor (PDGF) [50]. Furthermore, matrix metalloproteinase has been implicated in the remodeling of the extracellular matrix (ECM) of the heart [46,51]. Additionally, structural remodeling is mutually associated with AF: not only do structural remodeling events, such as fibrosis, promote AF, but AF itself also promotes cardiac fibrosis [52].

3. MicroRNAs (miRNAs)

MicroRNAs are a class of short (approximately 21–23 nts long), non-coding RNAs that bind to target mRNAs and participate in either translation repression or degradation, functioning as important post-transcriptional gene regulators [53]. In the genome, miRNAs are encoded as either intronic or intergenic miRNAs [54]. In the former case, miRNAs are processed from the introns of protein-coding gene transcripts, whereas they are transcribed under the control of their own promoters in the latter case. miRNA biogenesis begins with the transcription of a primary transcript, pri-miRNA, by RNA polymerase II in the nucleus. Pri-miRNAs, mRNA molecules that are generally thousands of nts long, are then processed by the ribonuclease III, Drosha, to produce a premature miRNA molecule (pre-miRNA) that is approximately 100 nt long and has a hairpin-like structure. The pre-miRNA is subsequently transferred to the cytosol by the nuclear export factor, exportin 5; the ribonuclease III, Dicer, processes this pre-miRNA further to generate a mature miRNA (for a detailed review of miRNA biogenesis, see [55]). Since they were first discovered in 1993 [56], miRNAs have been implicated in various diseases, including cardiovascular diseases [57,58,59]. According to a recent review (published in January 2014) regarding the role of miRNAs in AF, less than 10 miRNAs (miR-1, -21, -26, -29, -30, -133, -328 and -499) have been empirically associated with the regulation of the cardiac remodeling process [3]. However, our recent literature search for this particular review came up with additional miRNAs that may be involved in AF development; these miRNAs will be discussed in the corresponding section to come.
Regarding the influential range of miRNAs, recent studies have indicated that miRNAs might also exist as extracellular miRNAs. The known types of extracellular miRNAs are believed to be: (1) vesicle free; (2) apoptotic body enclosed; (3) vesicle shedding and exosome packaged; and (4) LDL associated [60]. Among these forms, the vesicle-free types, the apoptotic body-enclosed types and the exosome-packaged types are considered to be more relevant to oxidative injury/cell death situations. The apoptotic body-enclosed types are generated during apoptosis, as the name suggests. However, experimental data have suggested that the miRNAs contained in apoptotic bodies could function as an anti-inflammatory mechanism, rather than as a source of inflammation [61]. In contrast, the vesicle-free types have been suggested to be released passively by cell lysis in the form of complexes with Ago proteins during cell death [62], and for the exosome-packaged types, their release has been reported to be enhanced by oxidative stress [63]. It was demonstrated that miRNAs could bind to single-stranded, RNA-sensing Toll-like receptors (TLRs), such as TLR8 [64]. Because TLRs are important mediators of innate immunity [65], extracellular miRNA-mediated local inflammatory response and subsequent damage to surrounding tissue can occur. In fact, extracellular miRNAs, such as let-7, miR-21 and miR-29a, have been reported to induce an inflammatory response by binding to TLRs [66,67]. These data suggest that the range that is influenced by ROS-mediated regulation of miRNAs might not be limited to the cells directly exposed to ROS, and the impact of ROS-mediated regulation of miRNA might be greater than it appears.

4. Reactive Oxygen Species (ROS)

Oxidative stress has been implicated in the development and progression of various human diseases, including cardiovascular diseases, and is associated with excess ROS production [68,69]. The heart consumes a large amount of oxygen to maintain essential cellular functions and aerobic metabolism, during which both adenosine triphosphate (ATP) and ROS are generated in mitochondria [70]. ROS include a number of highly-reactive, free, non-radical and partially-reduced oxygen metabolites, such as the superoxide anion radical (·O2−), nitric oxide (NO), peroxynitrite (ONOO−) and hydrogen peroxide (H2O2) [71].
ROS participate in several important cellular signaling pathways as second messengers of growth factors and cytokines and also regulate gene expression by modulating transcription factors [72,73]. The increases in ROS are caused by an imbalance between ROS-producing enzymes (i.e., nicotinamide adenine dinucleotide phosphate, or NAD[P]H-oxidase, xanthine oxidase, the mitochondrial electron-transport chain and dysfunctional uncoupled eNOS) and antioxidant enzymes (i.e., superoxide dismutase (SOD), catalase, glutathione peroxidase, heme oxygenase and paraoxonase) [74]. The high rate of ROS production causes cell damage and death by impairing DNA, protein, cell membrane and cellular organelle functions, leading to the development of cardiovascular disease [75,76]. In the case of AF, various ROS molecules target arrhythmogenic molecules, including CaMKII [77], RyR2 [78] and LTCC [79] (for a more comprehensive review of the role of ROS in AF, see [80]).
ROS, such as superoxide and H2O2, are also known to modulate the generation of nitrogen oxide (NO) by regulating nitric oxide synthase (NOS). For example, H2O2 either increases or decreases endothelial NOS activity, depending on its concentration [81,82,83]. Furthermore, superoxide reacts with NO to produce peroxynitrite [84]. Peroxynitrite can induce the uncoupling of NOS, thus decreasing the bioavailability of NO [85], which can impair normal heart function [86]. Because the important role of NO in the development of AF has long been recognized [87,88], the redox balance achieved by these ROS is expected to have a significant impact on the development of AF.
Additionally, in a study using isolated animal hearts, the causal role of oxidative stress in AF was demonstrated [89]. However, in humans, it is virtually impossible to conduct an experiment that could directly show the cause and effect relationship between ROS and AF. Consequently, most of the available human data indicating the involvement of ROS in the development of AF are analyses of clinical, observational outcomes in patients (i.e., correlations between oxidative stress markers in AF patients [90] or pro- and anti-oxidant gene expression analyses in AF patients [91]). Additionally, less than satisfactory clinical results of ROS scavengers in treating AF [92] indicated that ROS might not be the single most important factor in the development of AF in humans. Thus, if we had to summarize, based on our current understanding on the subject, we would assert the following: although there is ample empirical evidence (of mostly animal studies) identifying ROS as the cause of AF, because AF in humans is a complex disease with a multifactorial etiology, it cannot be simply stated that ROS is definitively the most important factor responsible for the development of AF in humans.

5. ROS, miRNA and AF

Accumulating evidence indicates that miRNAs play an essential role in arrhythmogenesis [93]. To catch up with recent advances in miRNA-mediated arrhythmogenesis, we conducted a literature search in PubMed, using miRNA and arrhythmia as key words. Among the 130 articles we found (as of 10 October 2014), reviews and articles with irrelevant contents were excluded, as only original articles with relevant content were selected for this particular review. Key miRNAs that have been implicated or may be potentially involved in arrhythmogenesis are summarized in Table 1. Individual miRNAs implicated in AF pathogenesis by modulating electrical and structural remodeling processes are discussed in detail below.
Table
Table 1. miRNAs with reported or possible associations with atrial fibrillation (AF).
Table 1. miRNAs with reported or possible associations with atrial fibrillation (AF).
miRNAChanges in CVDs (Ref. if miR Expression Was Confirmed in Other Study)Targeted Protein (mRNA) and Subsequent ResultsRef.
miR-1Decreased in AFPotassium channel, inwardly rectifying, Kir2.1 (KCNJ2)Increased Ik1[94]
Decreased in hypertrophyConnexin 43 (GJA1)Cx43 displacement due to hyper-phosphorylation[95]
Increased in HF ([96])Protein phosphatase 2A (PPP2CA)Excessive RyR2 phosphorylation by CaMKII[97]
miR-19aIncreased in AF ([98])Phosphatase and tensin homolog (PTEN)Increased hypertrophy[99]
Connexin 43 (GJA1)Disturbed electrical coupling
miR-21Increased in MI Increased in AFSprouty1 (SPRY1)Increased fibrosis[100]
Calcium channel, voltage-dependent, l type, alpha 1C subunit (CACNA1C)Shortened APD[101]
Calcium channel, voltage-dependent, beta 2 subunit (CACNB2)Decreased ICaL
mir-26Decreased in AFPotassium channel, inwardly rectifying, Kir2.1 (KCNJ2)Increased Ik1[102]
miR-29bDecreased in CHF Collagen, type I, alpha 1 (COL1A1)Increased fibrosis[103]
Collagen, type III, alpha 1 (COL3A1)
Fibrillin (FBN)
miR-30Reduced in AF ([104])Connective tissue growth factor (CTGF)Increased fibrosis[105]
mir-130aIncreased in Atherosclerosis ([106])Connexin 43 (GJA1)Disturbed electrical coupling[107]
miR-133Reduced in AF ([104])Connective tissue growth factor (CTGF)Increased fibrosis[105]
Increased in HF ([96])Protein phosphatase 2A (PPP2CA)Excessive RyR2 phosphorylation by CaMKII[97]
miR-145Decreased in AF ([108])Ca2+/calmodulin-dependent protein kinase 2 delta (CAMK2D)Excessive RyR2 phosphorylation by CaMKII[109]
miR-328Increased in AFCalcium channel, voltage-dependent, l-Type, alpha 1C subunit (CACNA1C)Shortened APD[108]
Increased in hypertrophy ([ 110])Calcium channel, voltage-dependent, beta 1 subunit (CACNB1)Decreased ICaL[111]
miR-499Increased in AFSmall-conductance calcium-activated potassium channel 3 (KCNN3)Altered conduction[112]
Increased in hypertrophy ([113])Increased AF
Let-7eDecreased in Acute MIBeta 1 adrenergic receptor (ADRB1)Increased arrhythmia score[114]
AF, atrial fibrillation; HF, heart failure; MI, myocardial infarction; CHF, congestive heart failure; APD, action potential duration.

5.1. miRNAs that Likely Contribute to Arrhythmogenesis

5.1.1. miR-1

Among the conduction- and membrane potential-related ion channels of cardiomyocytes, GJA1 (encodes connexin 43, Cx43) and KCNJ2 (encodes K+ channel subunit Kir2.1) are targeted by miR-1. miR-1 expression is reportedly decreased in AF, allowing for increased IK1 activity, which is mediated by Kir2.1 [94]. Decreased miR-1 expression has also been reported in cardiac hypertrophy, a decrease that resulted in tachyarrhythmia due to the hyper-phosphorylation of Cx43 and subsequent Cx43 displacement [95]. These studies demonstrated the importance of miR-1 regulation in the electrical remodeling of the heart.
Another possible mechanism of miR-1-mediated arrhythmogenesis was proposed by Teremtuev et al. In their over-expression study, increased miR-1 levels in cardiac myocytes resulted in selective decreases in the expression of the B56α regulatory subunit of protein phosphatase 2A (PP2A), which mediates LTCC and RyR2 dephosphorylation. This decrease consequently increased the phosphorylation of LTCC and RyR2 in a CaMKII-dependent manner and resulted in significant increases in inward Ca2+ current (ICa) and Ca2+ release from the SR [97]. In fact, such an miR-1-mediated arrhythmogenic mechanism was confirmed in a heart failure model a few years later [96]. As both a decrease and an increase in miR-1 contributed to arrhythmogenesis, the findings of this study may seem contradictory. However, they may also indicate that the underlying pathologic conditions of the heart that lead to arrhythmogenesis can vary and that different conditions employ different mechanisms of utilizing miRNA; therefore, even a single miRNA may be regulated differently in the setting of different pathological conditions of the heart.

5.1.2. miR-19a (miR-17-92 Cluster)

The miR-17-92 cluster consists of the following six mature miRNAs: miR-17, -18a, -19a, -19b, -20a and -92a [115]. The roles of miR-17-92 in cardiovascular diseases, including arrhythmias, have been not well elucidated compared with cancer pathogenesis [116]. The expression of miR-19a, one of the members of the miR-17-92 cluster, is reportedly increased in the plasma of patients with AF [98]. Furthermore, when over-expressed in mice, the miR-17-92 cluster, including miR-19a/b, repressed the expression of PTEN, which regulates cardiomyocyte structure, size and contractility [117], and Cx43, which eventually resulted in premature sudden death [99]. Such results suggested that the miR-17-92 cluster was involved in both electrical and structural remodeling processes.

5.1.3. miR-21

In a rat model of myocardial infarction (MI), the level of atrial miR-21 expression increased, which was accompanied by increased left ventricular enlargement, hypo-contractility, left atrial dilation, fibrosis, refractory period prolongation and AF [100]. In that particular study, miR-21 promoted fibrotic remodeling following myocardial infarction by down-regulating Sprouty-1 (Spry1), a protein known to suppress fibroblast proliferation [118], to negatively regulate extracellular signal-regulated kinases 1/2 (ERK1/2) [119] and to up-regulate collagen-1 and 3 expression. According to a recent study, increased miR-21 expression was believed to result in the down-regulation of dual-specificity phosphatase 8 (DUSP8), a negative regulator of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38) [120], leading to the promotion of collagen synthesis in cardiac fibroblasts [121]. In another study, in the cardiomyocytes of patients with chronic AF, miR-21 expression increased, which resulted in the subsequent down-regulation of two subunits of a voltage-dependent calcium channel, specifically subunits 1αC (CACNA1C) and β2 (CACNB2), resulting in reduced l-Type Ca2+ current (ICaL) [101]. As reduced ICaL activity is one of the hallmarks of AF [15], this study demonstrated that miR-21 can be pro-arrhythmogenic and can modulate the electrical remodeling of cardiomyocytes.

5.1.4. miR-26

It has been reported that miR-26 also targets Kir2.1 and is down-regulated in humans and animals with AF. The decrease in miR-26a expression induced IK1 dysregulation via Kir2.1 expression, which is related to AF susceptibility. Interestingly, the AF-induced miR-26 decrease was mediated by a Ca2+-dependent transcription factor, nuclear factor of activated T-cells (NFAT) [102]. As increased IK1 activity is commonly observed in AF [27,28], miR-26 is believed to contribute to AF development by participating in the electrical remodeling of cardiomyocytes.

5.1.5. miR-29b

Dawson et al. reported that miR-29b expression decreased rapidly in the left atrial tissues studied in a congestive heart failure (CHF)-related AF model involving canines. [103]. The major targets of miR-29b identified in that study were ECM-coding genes, such as COL1A1, COL3A1 and FBN (encodes fibrillin); these genes were up-regulated in CHF fibroblasts due to decreased miR-29b expression. The expression of this miRNA is believed to be controlled by TGF-β-mediated NF-κB activation, because TGF-β expression is up-regulated in the arrhythmogenic atria of both animals and humans [122,123]. These studies indicate that miR-29 is involved in AF-related structural remodeling.

5.1.6. miR-30

Connective tissue growth factor (CTGF) is an important molecule in fibrosis progression, and its expression is reportedly regulated by two miRNAs, miR-30 and -133 [105]. In that study, both miR-30 and -133 expression levels were decreased in pathological left ventricular hypertrophy, which led to the promotion of collagen synthesis via CTGF up-regulation. Down-regulation of miR-30 and -133 in AF was further confirmed in another study by Li et al. [104]. These results indicate that both miR-30 and -133 modulate structural remodeling in AF by regulating fibrotic proteins.

5.1.7. miR-130a

Along with miR-27b and -210, -130a is reportedly increased in the serum in atherosclerosis obliterans [106]. Cardiac-specific overexpression of miR-130a in transgenic (Tg) mice resulted in decreased fractional shortening and in irregular heart rhythms, which were noted via echocardiographic analysis; compared with normal mice, miR-130a Tg mice demonstrated the following typical characteristics of atrial tachyarrhythmia: an irregular ventricular rate and rapid arterial activity in simultaneous surface and intracardiac electrocardiograms. These negative effects of ectopic miR-130a expression were linked to reduced Cx43 protein expression [107]. This study demonstrated that by modulating the expression of Cx43, miR-130a contributes to both electrical remodeling and the development of cardiac arrhythmias.

5.1.8. miR-133

In addition to contributing to the fibrotic structural remodeling of cardiomyocytes by targeting CTGF (see Section 5.1.6. above), miR-133 also targets the B56α regulatory subunit, PP2A, as does miR-1 (see Section 5.1.1. above). Resultant increases in LTCC and RyR2 phosphorylation caused significant increases in ICa activity and Ca2+ release from the SR in a heart failure model [96]. These studies suggest that miR-133 is involved in both the structural and the electrical remodeling of cardiomyocytes in the setting of arrhythmogenesis, as is the case with miR-19a.

5.1.9. miR-145

CaMKIIδ is a target [109] of miR-145, the expression of which is reportedly decreased in AF [108]. As increased CaMKII activity and subsequent increases in RyR2 phosphorylation resulted in arrhythmogenic SR Ca2+ leakage [124], the increase in CaMKII expression caused by the down-regulation of miR-145 in AF is also believed to be pro-arrhythmogenic. Therefore, miR-145 is believed to be involved in the electrical remodeling of cardiomyocytes in the setting of AF.

5.1.10. miR-328

miR-328 has been linked to cardiac hypertrophy, although its underlying mechanisms of action remain elusive. In a previous study in which miR-328 over-expression was accompanied by a reduced SERCA2a level, an increased intracellular calcium concentration and an increased calcineurin protein level, the importance of miR-328 in cellular calcium handling was demonstrated [110]. Another study conducted on animals and patients with AF reported that miR-328 is aberrantly up-regulated and targets CACNA1C and CACNB1 in AF, which results in reduced ICaL activity and a shortage of APD [111]. Additionally, circulating levels of miR-328 were associated with increases in AF prevalence [125], suggesting the potential involvement of miR-328 in the electrical remodeling and calcium handling processes of AF.

5.1.11. miR-499

miR-499 is reportedly up-regulated in both human and murine cardiac hypertrophy and cardiopathy, is sufficient to cause heart failure in murine subjects and accelerates maladaptation to pressure overloading [113]. Regarding the role of miR-499 in AF, Ling et al. reported that miR-499 was increased in AF and targeted the small-conductance calcium-activated potassium channel 3 (SK3, encoded by KCNN3 [126]), contributing to the electrical remodeling characteristics of AF [112].

5.1.12. Let-7e

Beta-adrenergic receptors (β-ARs) are G-protein-coupled receptors and play important roles in the regulation of cardiac function and heart rate [127]. The involvement of β-ARs in AF development has been indirectly demonstrated by the effectiveness of β-blockers at preventing AF [128]. According to a paper published by Li et al., in a rat model of acute MI, β1-AR expression increased, whereas cardiac-enriched let-7 family miRNA expression levels decreased, indicating that β1-AR is a direct target of let-7e [114]. In the same study, β1-AR down-regulation by exogenous let-7e exerted an anti-arrhythmic effect in MI rats, suggesting that let-7e may represent a novel therapeutic target for ischemia-induced cardiac arrhythmia by modulating β1-AR expression.

5.2. AF-Related miRNAs and ROS

For this section, we conducted a literature review to find any reported or possible connection between the aforementioned AF-related miRNAs and ROS to determine whether it is possible that those miRNAs are modulated by ROS and that ROS-induced arrhythmogenesis is at least partially mediated by miRNAs. For the literature search, key words, such as ROS, hydrogen peroxide (or H2O2, the compound most commonly used to simulate ROS in vitro) and oxidative stress, were used, along with individual miRNAs. Known or plausible relationships between the AF-related miRNAs and ROS are summarized in Table 2.
Table
Table 2. Modulation of AF-related miRNAs by ROS.
Table 2. Modulation of AF-related miRNAs by ROS.
miRNAModulation by ROSStimulationExperimental SystemRef.
miR-1IncreasedH2O2 (50–400 µM)H9c2[129]
IncreasedH2O2 (100 µM, 6 h)NRCM[130]
DecreasedH2O2 (100 µM, 6 h)NRVM[131]
miR-19aDecreasedH2O2 (200 µM, 6 h)VSMC[132]
miR-21IncreasedH2O2 (10–100 µM, 6 h)NRCM[133]
IncreasedH2O2 (25–200 µM, 6 h)VSMC[132]
IncreasedH2O2 (100 µM, 6 h)NRVM[131]
miR-26IncreasedH2O2 (100 µM, 6 h)NRCM[130]
DecreasedH2O2 (200 µM, 6 h)VSMC[132]
miR-29bDecreasedH2O2 (200 µM, 6 h)VSMC[132]
miR-30DecreasedH2O2 (100 µM, 6 h)NRCM[134]
miR-130aDecreasedH2O2 (200 µM, 6 h)VSMC[132]
miR-133DecreasedH2O2 (100 µM, 24 h)NRCM[135]
DecreasedH2O2 (100 µM, 6 h)NRVM[131]
miR-145DecreasedH2O2 (50 µM, 0.5–8 h)NRVM[136]
miR-328DecreasedH2O2 (200 µM, 6 h)VSMC[132]
miR-499IncreasedH2O2 (50–200 µM, 6 h)NRVM[131]
Let-7eDecreasedH2O2 (50 µM, 1 h)HCT116 colon cancer cells[137]
IncreasedH2O2 (200 µM, 6 h)VSMC[132]
NRCM, neonatal rat cardiomyocytes; VSMC, vascular smooth muscle cells; NRVM, neonatal rat ventricular myocytes.
As shown in Table 2, in terms of expression levels in cardiomyocytes, more than half of the AF-related miRNAs (seven out of 12 miRNAs) were affected by the presence of ROS (H2O2). Additionally, the same number of miRNAs (seven out of 12 miRNAs, as well) reportedly changed their expression levels (i.e., were either up- or down-regulated) in response to H2O2 treatment in vascular smooth muscle cells (VSMCs). VSMCs are an important vascular cell line and contribute significantly to the pathogenesis of various cardiovascular diseases [138]. Therefore, given that a positive association between AF and vascular diseases, such as atherosclerosis, has been clinically established in population studies [139,140], it is not far-fetched to assume that even the ROS-dependent regulation of those AF-related miRNAs in VSMCs may predispose individuals to AF development. Because changes in the expression levels of a particular miRNA varied depending on the experimental conditions (i.e., cell types or H2O2 concentrations), it is difficult for this review to provide any generalized or conclusive evidence regarding the existence of a framework composed of ROS–miRNA–AF. However, given that key electrical remodeling-related molecules, such as CaMKII, RyR, LTCC, SERCA and NCX, are targeted by ROS [80] and that an entire array of miRNAs with the potential to affect the arrhythmogenic process (i.e., targeting ion channels [108]) has not been investigated regarding any possible ROS-dependent regulation, the odds of the existence of such an ROS–miRNA–AF framework in the setting of arrhythmogenesis are reasonably high (Figure 1).
Ijms 15 21754 g001 1024
Figure 1. Concept of the ROS–miRNA–AF framework.
Figure 1. Concept of the ROS–miRNA–AF framework.
Ijms 15 21754 g001

5.3. Perspective: Can ROS-Dependent Dysregulation of miRNA Really Cause AF in Humans?

In studies using animals, excessive ROS (i.e., 10–200 µM of H2O2; see Table 2) are used to simulate oxidative stress, which occurs when the amount of ROS exceeds the cell’s ability to cope with it, thus proving the concept. However, we do not believe that endogenous ROS reach such high levels frequently [141,142], and more importantly, the etiology of AF in humans is more complicated than simply being driven by a single factor, such as ROS. In fact, other factors, such as inflammation and myocardial fibrosis, are also known to promote AF in humans [143,144]. Thus, in our opinion, endogenous oxidative stress most likely acts both as one of the AF triggering factors and as a factor exacerbating AF. Consequently, we believe that most people do not develop AF, because the initiation of AF in humans requires more than just high levels of ROS, and pathological manifestations occur only when other pathological conditions are “unfortunately satisfied”.
Nevertheless, there is a possibility that one might be more susceptible to AF than another, depending on the genetic composition of the individual. In fact, a correlation between an SNP (single nucleotide polymorphism) and AF was reported [145]. Additionally, individual personal lifestyles can have effects on the probability of developing AF; smoking [146] and drinking [147] are good examples. Another theoretically possible case involving miRNAs is one having SNPs on the coding sequences of miRNAs involved in the regulation of AF development. Similar to SNPs on protein coding genes, SNPs on miRNA coding sequences can result in the demise of miRNA function [148]. Thus, in theory, SNP-induced dysregulation of miRNA in an individual can increase (or decrease) his or her susceptibility to AF, and a very recent study reported such a possibility [149].

6. Concluding Remarks

It should be noted that this review was mostly based on the results of experimental studies on animals. Because AF in humans is a complex disease with a multifactorial etiology (i.e., oxidative stress, inflammation and atherothromboembolism [150]), the outcomes of animal studies might not perfectly reflect the actual etiology of AF in humans, which is an obvious limitation of this review, as well as of most studies involving animal subjects in general, and readers should consider this point in interpreting this review. Another limitation of this review is that the number of publications regarding the ROS-dependent regulation of AF-related miRNAs was very limited; therefore, this review covered only the possible ROS-dependent regulation of those AF-related miRNAs discussed in earlier sections of this manuscript. However, the possibility that ROS affects miRNAs and that such ROS-dependent changes to miRNAs either directly or indirectly contribute to arrhythmogenesis still exists. Therefore, the aim of this review was to encourage scientific interest in discovering a conceptual framework composed of ROS–miRNA–AF that is related to arrhythmia development. Although this review could not provide hard evidence of any specific, detailed examples of such a framework, the fact that previously-described AF-related miRNAs changed in response to ROS was enough to suggest the possibility that miRNAs translate cellular stressors, such as ROS, into AF pathogenesis and warrants further study with a more appropriate experimental design to prove or disprove the existence of an ROS–miRNA–AF framework.

Acknowledgments

This study was supported by a Korea Science and Engineering Foundation grant funded by the Korean government (Ministry of Education, Science and Technology) (2014030459) and a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Korea (A120478).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Alpert, J.S. Atrial fibrillation: A growth industry in the 21st century. Eur. Heart J. 2000, 21, 1207–1208. [Google Scholar] [PubMed]
  2. Menezes, A.R.; Lavie, C.J.; DiNicolantonio, J.J.; O’Keefe, J.; Morin, D.P.; Khatib, S.; Milani, R.V. Atrial fibrillation in the 21st century: A current understanding of risk factors and primary prevention strategies. Mayo Clin. Proc. 2013, 88, 394–409. [Google Scholar] [CrossRef] [PubMed]
  3. Santulli, G.; Iaccarino, G.; de Luca, N.; Trimarco, B.; Condorelli, G. Atrial fibrillation and microRNAs. Front. Physiol. 2014, 5, 15. [Google Scholar] [CrossRef] [PubMed]
  4. Nattel, S.; Burstein, B.; Dobrev, D. Atrial remodeling and atrial fibrillation: Mechanisms and implications. Circ. Arrhythm. Electrophysiol. 2008, 1, 62–73. [Google Scholar] [CrossRef] [PubMed]
  5. Youn, J.Y.; Zhang, J.; Zhang, Y.; Chen, H.; Liu, D.; Ping, P.; Weiss, J.N.; Cai, H. Oxidative stress in atrial fibrillation: An emerging role of NADPH oxidase. J. Mol. Cell. Cardiol. 2013, 62, 72–79. [Google Scholar] [CrossRef] [PubMed]
  6. Magenta, A.; Greco, S.; Gaetano, C.; Martelli, F. Oxidative stress and microRNAs in vascular diseases. Int. J. Mol. Sci. 2013, 14, 17319–17346. [Google Scholar] [PubMed]
  7. Nattel, S.; Harada, M. Atrial remodeling and atrial fibrillation: Recent advances and translational perspectives. J. Am. Coll. Cardiol. 2014, 63, 2335–2345. [Google Scholar] [CrossRef] [PubMed]
  8. Heijman, J.; Voigt, N.; Dobrev, D. New directions in antiarrhythmic drug therapy for atrial fibrillation. Future Cardiol. 2013, 9, 71–88. [Google Scholar] [CrossRef]
  9. Wakili, R.; Voigt, N.; Kaab, S.; Dobrev, D.; Nattel, S. Recent advances in the molecular pathophysiology of atrial fibrillation. J. Clin. Investig. 2011, 121, 2955–2968. [Google Scholar] [CrossRef] [PubMed]
  10. Brundel, B.J.; van Gelder, I.C.; Henning, R.H.; Tuinenburg, A.E.; Wietses, M.; Grandjean, J.G.; Wilde, A.A.; van Gilst, W.H.; Crijns, H.J. Alterations in potassium channel gene expression in atria of patients with persistent and paroxysmal atrial fibrillation: Differential regulation of protein and mRNA levels for K+ channels. J. Am. Coll. Cardiol. 2001, 37, 926–932. [Google Scholar] [CrossRef] [PubMed]
  11. Bosch, R.F.; Zeng, X.; Grammer, J.B.; Popovic, K.; Mewis, C.; Kuhlkamp, V. Ionic mechanisms of electrical remodeling in human atrial fibrillation. Cardiovasc. Res. 1999, 44, 121–131. [Google Scholar] [CrossRef] [PubMed]
  12. Burstein, B.; Nattel, S. Atrial fibrosis: Mechanisms and clinical relevance in atrial fibrillation. J. Am. Coll. Cardiol. 2008, 51, 802–809. [Google Scholar] [CrossRef] [PubMed]
  13. Yeh, Y.H.; Wakili, R.; Qi, X.Y.; Chartier, D.; Boknik, P.; Kaab, S.; Ravens, U.; Coutu, P.; Dobrev, D.; Nattel, S. Calcium-handling abnormalities underlying atrial arrhythmogenesis and contractile dysfunction in dogs with congestive heart failure. Circ. Arrhythm. Electrophysiol. 2008, 1, 93–102. [Google Scholar] [CrossRef] [PubMed]
  14. Chen, P.S.; Tan, A.Y. Autonomic nerve activity and atrial fibrillation. Heart Rhythm 2007, 4, S61–S64. [Google Scholar] [CrossRef] [PubMed]
  15. Dinanian, S.; Boixel, C.; Juin, C.; Hulot, J.S.; Coulombe, A.; Rucker-Martin, C.; Bonnet, N.; le Grand, B.; Slama, M.; Mercadier, J.J.; et al. Downregulation of the calcium current in human right atrial myocytes from patients in sinus rhythm but with a high risk of atrial fibrillation. Eur. Heart J. 2008, 29, 1190–1197. [Google Scholar] [CrossRef] [PubMed]
  16. Zucchi, R.; Ronca-Testoni, S. The sarcoplasmic reticulum Ca2+ channel/ryanodine receptor: Modulation by endogenous effectors, drugs and disease states. Pharmacol. Rev. 1997, 49, 1–51. [Google Scholar] [PubMed]
  17. Shan, J.; Xie, W.; Betzenhauser, M.; Reiken, S.; Chen, B.X.; Wronska, A.; Marks, A.R. Calcium leak through ryanodine receptors leads to atrial fibrillation in 3 mouse models of catecholaminergic polymorphic ventricular tachycardia. Circ. Res. 2012, 111, 708–717. [Google Scholar] [CrossRef] [PubMed]
  18. MacLennan, D.H.; Asahi, M.; Tupling, A.R. The regulation of SERCA-type pumps by phospholamban and sarcolipin. Ann. N. Y. Acad. Sci. 2003, 986, 472–480. [Google Scholar] [CrossRef] [PubMed]
  19. Voigt, N.; Li, N.; Wang, Q.; Wang, W.; Trafford, A.W.; Abu-Taha, I.; Sun, Q.; Wieland, T.; Ravens, U.; Nattel, S.; et al. Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+–Ca2+ exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation. Circulation 2012, 125, 2059–2070. [Google Scholar] [CrossRef] [PubMed]
  20. Fischer, T.H.; Herting, J.; Tirilomis, T.; Renner, A.; Neef, S.; Toischer, K.; Ellenberger, D.; Forster, A.; Schmitto, J.D.; Gummert, J.; et al. Ca2+/calmodulin-dependent protein kinase II and protein kinase A differentially regulate sarcoplasmic reticulum Ca2+ leak in human cardiac pathology. Circulation 2013, 128, 970–981. [Google Scholar] [CrossRef] [PubMed]
  21. Hudasek, K.; Brown, S.T.; Fearon, I.M. H2O2 regulates recombinant Ca2+ channel alpha1C subunits but does not mediate their sensitivity to acute hypoxia. Biochem. Biophys. Res. Commun. 2004, 318, 135–141. [Google Scholar] [CrossRef] [PubMed]
  22. Morris, T.E.; Sulakhe, P.V. Sarcoplasmic reticulum Ca2+-pump dysfunction in rat cardiomyocytes briefly exposed to hydroxyl radicals. Free Radic. Biol. Med. 1997, 22, 37–47. [Google Scholar] [CrossRef] [PubMed]
  23. Goldhaber, J.I. Free radicals enhance Na+/Ca2+ exchange in ventricular myocytes. Am. J. Physiol. 1996, 271, H823–H833. [Google Scholar] [PubMed]
  24. Anzai, K.; Ogawa, K.; Ozawa, T.; Yamamoto, H. Oxidative modification of ion channel activity of ryanodine receptor. Antioxid. Redox Signal. 2000, 2, 35–40. [Google Scholar] [CrossRef] [PubMed]
  25. Dhamoon, A.S.; Jalife, J. The inward rectifier current (IK1) controls cardiac excitability and is involved in arrhythmogenesis. Heart Rhythm 2005, 2, 316–324. [Google Scholar] [CrossRef] [PubMed]
  26. Hibino, H.; Inanobe, A.; Furutani, K.; Murakami, S.; Findlay, I.; Kurachi, Y. Inwardly rectifying potassium channels: Their structure, function, and physiological roles. Physiol. Rev. 2010, 90, 291–366. [Google Scholar] [CrossRef] [PubMed]
  27. Atienza, F.; Almendral, J.; Moreno, J.; Vaidyanathan, R.; Talkachou, A.; Kalifa, J.; Arenal, A.; Villacastin, J.P.; Torrecilla, E.G.; Sanchez, A.; et al. Activation of inward rectifier potassium channels accelerates atrial fibrillation in humans: Evidence for a reentrant mechanism. Circulation 2006, 114, 2434–2442. [Google Scholar] [CrossRef]
  28. Dobrev, D.; Wettwer, E.; Kortner, A.; Knaut, M.; Schuler, S.; Ravens, U. Human inward rectifier potassium channels in chronic and postoperative atrial fibrillation. Cardiovas. Res. 2002, 54, 397–404. [Google Scholar] [CrossRef]
  29. Anumonwo, J.M.; Lopatin, A.N. Cardiac strong inward rectifier potassium channels. J. Mol. Cell. Cardiol. 2010, 48, 45–54. [Google Scholar] [CrossRef] [PubMed]
  30. Kovoor, P.; Wickman, K.; Maguire, C.T.; Pu, W.; Gehrmann, J.; Berul, C.I.; Clapham, D.E. Evaluation of the role of I(KACh) in atrial fibrillation using a mouse knockout model. J. Am. Coll. Cardiol. 2001, 37, 2136–2143. [Google Scholar] [CrossRef] [PubMed]
  31. Cha, T.J.; Ehrlich, J.R.; Chartier, D.; Qi, X.Y.; Xiao, L.; Nattel, S. Kir3-based inward rectifier potassium current: Potential role in atrial tachycardia remodeling effects on atrial repolarization and arrhythmias. Circulation 2006, 113, 1730–1737. [Google Scholar] [CrossRef] [PubMed]
  32. Wu, T.J.; Kim, Y.H.; Yashima, M.; Athill, C.A.; Ting, C.T.; Karagueuzian, H.S.; Chen, P.S. Progressive action potential duration shortening and the conversion from atrial flutter to atrial fibrillation in the isolated canine right atrium. J. Am. Coll. Cardiol. 2001, 38, 1757–1765. [Google Scholar] [CrossRef] [PubMed]
  33. Koo, S.H.; Wakili, R.; Heo, J.H.; Chartier, D.; Kim, H.S.; Kim, S.J.; Lee, J.W.; Qi, X.Y.; Nattel, S.; Cha, T.J. Role of constitutively active acetylcholine-mediated potassium current in atrial contractile dysfunction caused by atrial tachycardia remodelling. Europace 2010, 12, 1490–1497. [Google Scholar] [CrossRef] [PubMed]
  34. Li, M.L.; Li, T.; Lei, M.; Tan, X.Q.; Yang, Y.; Liu, T.P.; Pei, J.; Zeng, X.R. Increased small conductance calcium-activated potassium channel (SK2 channel) current in atrial myocytes of patients with persistent atrial fibrillation. Zhonghua Xin Xue Guan Bing Za Zhi 2011, 39, 147–151. (In Chinese) [Google Scholar] [PubMed]
  35. Qi, X.Y.; Diness, J.G.; Brundel, B.J.; Zhou, X.B.; Naud, P.; Wu, C.T.; Huang, H.; Harada, M.; Aflaki, M.; Dobrev, D.; et al. Role of small-conductance calcium-activated potassium channels in atrial electrophysiology and fibrillation in the dog. Circulation 2014, 129, 430–440. [Google Scholar] [CrossRef] [PubMed]
  36. Olson, T.M.; Alekseev, A.E.; Liu, X.K.; Park, S.; Zingman, L.V.; Bienengraeber, M.; Sattiraju, S.; Ballew, J.D.; Jahangir, A.; Terzic, A. Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum. Mol. Genet. 2006, 15, 2185–2191. [Google Scholar] [CrossRef] [PubMed]
  37. Bilodeau, M.T.; Trotter, B.W. Kv1.5 blockers for the treatment of atrial fibrillation: Approaches to optimization of potency and selectivity and translation to in vivo pharmacology. Curr. Top. Med. Chem. 2009, 9, 436–451. [Google Scholar] [CrossRef]
  38. Tamargo, J.; Caballero, R.; Gomez, R.; Delpon, E. I(Kur)/Kv1.5 channel blockers for the treatment of atrial fibrillation. Expert Opin. Investig. Drugs 2009, 18, 399–416. [Google Scholar] [CrossRef] [PubMed]
  39. Caouette, D.; Dongmo, C.; Berube, J.; Fournier, D.; Daleau, P. Hydrogen peroxide modulates the Kv1.5 channel expressed in a mammalian cell line. Naunyn-Schmied. Arch. Pharmacol. 2003, 368, 479–486. [Google Scholar] [CrossRef]
  40. Kolbe, K.; Schonherr, R.; Gessner, G.; Sahoo, N.; Hoshi, T.; Heinemann, S.H. Cysteine 723 in the C-linker segment confers oxidative inhibition of hERG1 potassium channels. J. Physiol. 2010, 588, 2999–3009. [Google Scholar] [PubMed]
  41. Dhein, S. Pharmacology of gap junctions in the cardiovascular system. Cardiovasc. Res. 2004, 62, 287–298. [Google Scholar] [CrossRef] [PubMed]
  42. Saffitz, J.E. Connexins, conduction, and atrial fibrillation. N. Engl. J. Med. 2006, 354, 2712–2714. [Google Scholar] [CrossRef] [PubMed]
  43. Kato, T.; Iwasaki, Y.K.; Nattel, S. Connexins and atrial fibrillation: Filling in the gaps. Circulation 2012, 125, 203–206. [Google Scholar] [CrossRef] [PubMed]
  44. Casaclang-Verzosa, G.; Gersh, B.J.; Tsang, T.S. Structural and functional remodeling of the left atrium: Clinical and therapeutic implications for atrial fibrillation. J. Am. Coll. Cardiol. 2008, 51, 1–11. [Google Scholar] [CrossRef] [PubMed]
  45. Corradi, D.; Callegari, S.; Maestri, R.; Benussi, S.; Alfieri, O. Structural remodeling in atrial fibrillation. Nat. Clin. Pract. Cardiovasc. Med. 2008, 5, 782–796. [Google Scholar] [CrossRef] [PubMed]
  46. Khan, A.; Moe, G.W.; Nili, N.; Rezaei, E.; Eskandarian, M.; Butany, J.; Strauss, B.H. The cardiac atria are chambers of active remodeling and dynamic collagen turnover during evolving heart failure. J. Am. Coll. Cardiol. 2004, 43, 68–76. [Google Scholar] [CrossRef] [PubMed]
  47. Burstein, B.; Comtois, P.; Michael, G.; Nishida, K.; Villeneuve, L.; Yeh, Y.H.; Nattel, S. Changes in connexin expression and the atrial fibrillation substrate in congestive heart failure. Circ. Res. 2009, 105, 1213–1222. [Google Scholar] [CrossRef] [PubMed]
  48. Weber, K.T.; Brilla, C.G.; Campbell, S.E.; Guarda, E.; Zhou, G.; Sriram, K. Myocardial fibrosis: Role of angiotensin II and aldosterone. Basic Res. Cardiol. 1993, 88, 107–124. [Google Scholar] [PubMed]
  49. Lijnen, P.J.; Petrov, V.V.; Fagard, R.H. Induction of cardiac fibrosis by transforming growth factor-beta(1). Mol. Genet. Metab. 2000, 71, 418–435. [Google Scholar] [CrossRef] [PubMed]
  50. Ponten, A.; Folestad, E.B.; Pietras, K.; Eriksson, U. Platelet-derived growth factor D induces cardiac fibrosis and proliferation of vascular smooth muscle cells in heart-specific transgenic mice. Circ. Res. 2005, 97, 1036–1045. [Google Scholar] [CrossRef] [PubMed]
  51. Boixel, C.; Fontaine, V.; Rucker-Martin, C.; Milliez, P.; Louedec, L.; Michel, J.B.; Jacob, M.P.; Hatem, S.N. Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat. J. Am. Coll. Cardiol. 2003, 42, 336–344. [Google Scholar] [CrossRef] [PubMed]
  52. Burstein, B.; Qi, X.Y.; Yeh, Y.H.; Calderone, A.; Nattel, S. Atrial cardiomyocyte tachycardia alters cardiac fibroblast function: A novel consideration in atrial remodeling. Cardiovasc. Res. 2007, 76, 442–452. [Google Scholar] [CrossRef] [PubMed]
  53. Sevignani, C.; Calin, G.A.; Siracusa, L.D.; Croce, C.M. Mammalian microRNAs: A small world for fine-tuning gene expression. Mamm. Genome 2006, 17, 189–202. [Google Scholar] [CrossRef] [PubMed]
  54. Bartel, D.P. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 2004, 116, 281–297. [Google Scholar] [CrossRef] [PubMed]
  55. Ha, M.; Kim, V.N. Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 2014, 15, 509–524. [Google Scholar] [CrossRef] [PubMed]
  56. Lee, R.C.; Feinbaum, R.L.; Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993, 75, 843–854. [Google Scholar] [CrossRef] [PubMed]
  57. Ardekani, A.M.; Naeini, M.M. The role of microRNAs in human diseases. Avicenna J. Med. Biotechnol. 2010, 2, 161–179. [Google Scholar] [PubMed]
  58. Small, E.M.; Frost, R.J.; Olson, E.N. MicroRNAs add a new dimension to cardiovascular disease. Circulation 2010, 121, 1022–1032. [Google Scholar] [CrossRef] [PubMed]
  59. Condorelli, G.; Latronico, M.V.; Cavarretta, E. MicroRNAs in cardiovascular diseases: Current knowledge and the road ahead. J. Am. Coll. Cardiol. 2014, 63, 2177–2187. [Google Scholar] [CrossRef] [PubMed]
  60. Turchinovich, A.; Weiz, L.; Burwinkel, B. Extracellular miRNAs: The mystery of their origin and function. Trends Biochem. Sci. 2012, 37, 460–465. [Google Scholar] [CrossRef] [PubMed]
  61. Zernecke, A.; Bidzhekov, K.; Noels, H.; Shagdarsuren, E.; Gan, L.; Denecke, B.; Hristov, M.; Koppel, T.; Jahantigh, M.N.; Lutgens, E.; et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci. Signal. 2009, 2, ra81. [Google Scholar] [CrossRef] [PubMed]
  62. Turchinovich, A.; Weiz, L.; Langheinz, A.; Burwinkel, B. Characterization of extracellular circulating microRNA. Nucleic Acids Res. 2011, 39, 7223–7233. [Google Scholar] [CrossRef] [PubMed]
  63. Hedlund, M.; Nagaeva, O.; Kargl, D.; Baranov, V.; Mincheva-Nilsson, L. Thermal- and oxidative stress causes enhanced release of NKG2D ligand-bearing immunosuppressive exosomes in leukemia/lymphoma T and B cells. PLoS One 2011, 6, e16899. [Google Scholar] [CrossRef] [PubMed]
  64. Fabbri, M. TLRs as miRNA receptors. Cancer Res. 2012, 72, 6333–6337. [Google Scholar] [CrossRef] [PubMed]
  65. Olivieri, F.; Rippo, M.R.; Prattichizzo, F.; Babini, L.; Graciotti, L.; Recchioni, R.; Procopio, A.D. Toll like receptor signaling in “inflammaging”: microRNA as new players. Immun. Ageing 2013, 10, 11. [Google Scholar] [PubMed]
  66. Ohshima, K.; Inoue, K.; Fujiwara, A.; Hatakeyama, K.; Kanto, K.; Watanabe, Y.; Muramatsu, K.; Fukuda, Y.; Ogura, S.; Yamaguchi, K.; et al. Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. PLoS One 2010, 5, e13247. [Google Scholar] [CrossRef] [PubMed]
  67. Fabbri, M.; Paone, A.; Calore, F.; Galli, R.; Gaudio, E.; Santhanam, R.; Lovat, F.; Fadda, P.; Mao, C.; Nuovo, G.J.; et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc. Natl. Acad. Sci. USA 2012, 109, E2110–E2116. [Google Scholar] [CrossRef] [PubMed]
  68. Bhatt, D.L.; Pashkow, F.J. Introduction. Oxidative stress and heart disease. Am. J. Cardiol. 2008, 101, 1D–2D. [Google Scholar] [CrossRef] [PubMed]
  69. Ogura, S.; Shimosawa, T. Oxidative stress and organ damages. Curr. Hypertens. Rep. 2014, 16, 452. [Google Scholar] [CrossRef] [PubMed]
  70. Chen, Y.R.; Zweier, J.L. Cardiac mitochondria and reactive oxygen species generation. Circ. Res. 2014, 114, 524–537. [Google Scholar] [CrossRef] [PubMed]
  71. Giordano, F.J. Oxygen, oxidative stress, hypoxia, and heart failure. J. Clin. Investig. 2005, 115, 500–508. [Google Scholar] [CrossRef] [PubMed]
  72. Thannickal, V.J.; Fanburg, B.L. Reactive oxygen species in cell signaling. Am. J. Physiol. Lung Cell. Mol. Physiol. 2000, 279, L1005–L1028. [Google Scholar] [PubMed]
  73. Hong, S.Y.; Roze, L.V.; Linz, J.E. Oxidative stress-related transcription factors in the regulation of secondary metabolism. Toxins 2013, 5, 683–702. [Google Scholar] [CrossRef] [PubMed]
  74. Li, H.; Horke, S.; Forstermann, U. Oxidative stress in vascular disease and its pharmacological prevention. Trends Pharmacol. Sci. 2013, 34, 313–319. [Google Scholar] [CrossRef] [PubMed]
  75. Ceconi, C.; Boraso, A.; Cargnoni, A.; Ferrari, R. Oxidative stress in cardiovascular disease: Myth or fact? Arch. Biochem. Biophys. 2003, 420, 217–221. [Google Scholar] [CrossRef] [PubMed]
  76. Otani, H. Oxidative stress as pathogenesis of cardiovascular risk associated with metabolic syndrome. Antioxid. Redox Signal. 2011, 15, 1911–1926. [Google Scholar] [CrossRef] [PubMed]
  77. Sepulveda, M.; Gonano, L.A.; Back, T.G.; Chen, S.R.; Vila Petroff, M. Role of CaMKII and ROS in rapid pacing-induced apoptosis. J. Mol. Cell. Cardiol. 2013, 63, 135–145. [Google Scholar] [CrossRef] [PubMed]
  78. Donoso, P.; Sanchez, G.; Bull, R.; Hidalgo, C. Modulation of cardiac ryanodine receptor activity by ROS and RNS. Front. Biosci. 2011, 16, 553–567. [Google Scholar] [CrossRef]
  79. Amberg, G.C.; Earley, S.; Glapa, S.A. Local regulation of arterial l-type calcium channels by reactive oxygen species. Circ. Res. 2010, 107, 1002–1010. [Google Scholar] [CrossRef] [PubMed]
  80. Sovari, A.A.; Dudley, S.C., Jr. Reactive oxygen species-targeted therapeutic interventions for atrial fibrillation. Front. Physiol. 2012, 3, 311. [Google Scholar] [CrossRef] [PubMed]
  81. Thomas, S.R.; Chen, K.; Keaney, J.F., Jr. Hydrogen peroxide activates endothelial nitric-oxide synthase through coordinated phosphorylation and dephosphorylation via a phosphoinositide 3-kinase-dependent signaling pathway. J. Biol. Chem. 2002, 277, 6017–6024. [Google Scholar] [CrossRef] [PubMed]
  82. Kumar, S.; Sun, X.; Wedgwood, S.; Black, S.M. Hydrogen peroxide decreases endothelial nitric oxide synthase promoter activity through the inhibition of AP-1 activity. Am. J. Physiol. Lung Cell. Mol. Physiol. 2008, 295, L370–L377. [Google Scholar] [CrossRef]
  83. Kumar, S.; Sun, X.; Wiseman, D.A.; Tian, J.; Umapathy, N.S.; Verin, A.D.; Black, S.M. Hydrogen peroxide decreases endothelial nitric oxide synthase promoter activity through the inhibition of Sp1 activity. DNA Cell Biol. 2009, 28, 119–129. [Google Scholar] [CrossRef] [PubMed]
  84. Jourd’heuil, D.; Jourd’heuil, F.L.; Kutchukian, P.S.; Musah, R.A.; Wink, D.A.; Grisham, M.B. Reaction of superoxide and nitric oxide with peroxynitrite. Implications for peroxynitrite-mediated oxidation reactions in vivo. J. Biol. Chem. 2001, 276, 28799–28805. [Google Scholar] [CrossRef] [PubMed]
  85. Lee, D.Y.; Wauquier, F.; Eid, A.A.; Roman, L.J.; Ghosh-Choudhury, G.; Khazim, K.; Block, K.; Gorin, Y. Nox4 NADPH oxidase mediates peroxynitrite-dependent uncoupling of endothelial nitric-oxide synthase and fibronectin expression in response to angiotensin II: Role of mitochondrial reactive oxygen species. J. Biol. Chem. 2013, 288, 28668–28686. [Google Scholar] [CrossRef] [PubMed]
  86. Silberman, G.A.; Fan, T.H.; Liu, H.; Jiao, Z.; Xiao, H.D.; Lovelock, J.D.; Boulden, B.M.; Widder, J.; Fredd, S.; Bernstein, K.E.; et al. Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction. Circulation 2010, 121, 519–528. [Google Scholar] [CrossRef] [PubMed]
  87. Dudley, S.C., Jr.; Hoch, N.E.; McCann, L.A.; Honeycutt, C.; Diamandopoulos, L.; Fukai, T.; Harrison, D.G.; Dikalov, S.I.; Langberg, J. Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: Role of the NADPH and xanthine oxidases. Circulation 2005, 112, 1266–1273. [Google Scholar] [CrossRef]
  88. Rubart, M.; Zipes, D.P. NO hope for patients with atrial fibrillation. Circulation 2002, 106, 2764–2766. [Google Scholar] [CrossRef] [PubMed]
  89. Morita, N.; Sovari, A.A.; Xie, Y.; Fishbein, M.C.; Mandel, W.J.; Garfinkel, A.; Lin, S.F.; Chen, P.S.; Xie, L.H.; Chen, F.; et al. Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress. Am. J. Physiol. Heart Circ. Physiol. 2009, 297, H1594–H1605. [Google Scholar] [CrossRef] [PubMed]
  90. Neuman, R.B.; Bloom, H.L.; Shukrullah, I.; Darrow, L.A.; Kleinbaum, D.; Jones, D.P.; Dudley, S.C., Jr. Oxidative stress markers are associated with persistent atrial fibrillation. Clin. Chem. 2007, 53, 1652–1657. [Google Scholar] [CrossRef] [PubMed]
  91. Kim, Y.H.; Lim, D.S.; Lee, J.H.; Shim, W.J.; Ro, Y.M.; Park, G.H.; Becker, K.G.; Cho-Chung, Y.S.; Kim, M.K. Gene expression profiling of oxidative stress on atrial fibrillation in humans. Exp. Mol. Med. 2003, 35, 336–349. [Google Scholar] [CrossRef] [PubMed]
  92. Sovari, A.A.; Dudley, S.C. Antioxidant therapy for atrial fibrillation: Lost in translation? Heart 2012, 98, 1615–1616. [Google Scholar] [CrossRef] [PubMed]
  93. Kim, G.H. MicroRNA regulation of cardiac conduction and arrhythmias. Transl. Res. 2013, 161, 381–392. [Google Scholar] [CrossRef] [PubMed]
  94. Girmatsion, Z.; Biliczki, P.; Bonauer, A.; Wimmer-Greinecker, G.; Scherer, M.; Moritz, A.; Bukowska, A.; Goette, A.; Nattel, S.; Hohnloser, S.H.; et al. Changes in microRNA-1 expression and IK1 up-regulation in human atrial fibrillation. Heart Rhythm 2009, 6, 1802–1809. [Google Scholar] [CrossRef] [PubMed]
  95. Curcio, A.; Torella, D.; Iaconetti, C.; Pasceri, E.; Sabatino, J.; Sorrentino, S.; Giampa, S.; Micieli, M.; Polimeni, A.; Henning, B.J.; et al. MicroRNA-1 downregulation increases connexin 43 displacement and induces ventricular tachyarrhythmias in rodent hypertrophic hearts. PLoS One 2013, 8, e70158. [Google Scholar] [CrossRef] [PubMed]
  96. Belevych, A.E.; Sansom, S.E.; Terentyeva, R.; Ho, H.T.; Nishijima, Y.; Martin, M.M.; Jindal, H.K.; Rochira, J.A.; Kunitomo, Y.; Abdellatif, M.; et al. MicroRNA-1 and -133 increase arrhythmogenesis in heart failure by dissociating phosphatase activity from RyR2 complex. PLoS One 2011, 6, e28324. [Google Scholar] [CrossRef]
  97. Terentyev, D.; Belevych, A.E.; Terentyeva, R.; Martin, M.M.; Malana, G.E.; Kuhn, D.E.; Abdellatif, M.; Feldman, D.S.; Elton, T.S.; Gyorke, S. miR-1 overexpression enhances Ca2+ release and promotes cardiac arrhythmogenesis by targeting PP2A regulatory subunit B56alpha and causing CaMKII-dependent hyperphosphorylation of RyR2. Circ. Res. 2009, 104, 514–521. [Google Scholar] [CrossRef] [PubMed]
  98. Liu, Z.; Zhou, C.; Liu, Y.; Wang, S.; Ye, P.; Miao, X.; Xia, J. The expression levels of plasma micoRNAs in atrial fibrillation patients. PLoS One 2012, 7, e44906. [Google Scholar] [CrossRef] [PubMed]
  99. Danielson, L.S.; Park, D.S.; Rotllan, N.; Chamorro-Jorganes, A.; Guijarro, M.V.; Fernandez-Hernando, C.; Fishman, G.I.; Phoon, C.K.; Hernando, E. Cardiovascular dysregulation of miR-17–92 causes a lethal hypertrophic cardiomyopathy and arrhythmogenesis. FASEB J. 2013, 27, 1460–1467. [Google Scholar] [CrossRef] [PubMed]
  100. Cardin, S.; Guasch, E.; Luo, X.; Naud, P.; le Quang, K.; Shi, Y.; Tardif, J.C.; Comtois, P.; Nattel, S. Role for MicroRNA-21 in atrial profibrillatory fibrotic remodeling associated with experimental postinfarction heart failure. Circ. Arrhythm. Electrophysiol. 2012, 5, 1027–1035. [Google Scholar] [CrossRef] [PubMed]
  101. Barana, A.; Matamoros, M.; Dolz-Gaiton, P.; Perez-Hernandez, M.; Amoros, I.; Nunez, M.; Sacristan, S.; Pedraz, A.; Pinto, A.; Fernandez-Aviles, F.; et al. Chronic atrial fibrillation increases microRNA-21 in human atrial myocytes decreasing l-type calcium current. Circ. Arrhythm. Electrophysiol. 2014, 7, 861–868. [Google Scholar] [CrossRef] [PubMed]
  102. Luo, X.; Pan, Z.; Shan, H.; Xiao, J.; Sun, X.; Wang, N.; Lin, H.; Xiao, L.; Maguy, A.; Qi, X.Y.; et al. MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation. J. Clin. Investig. 2013, 123, 1939–1951. [Google Scholar] [CrossRef] [PubMed]
  103. Dawson, K.; Wakili, R.; Ordog, B.; Clauss, S.; Chen, Y.; Iwasaki, Y.; Voigt, N.; Qi, X.Y.; Sinner, M.F.; Dobrev, D.; et al. MicroRNA29: A mechanistic contributor and potential biomarker in atrial fibrillation. Circulation 2013, 127. [Google Scholar] [CrossRef] [PubMed]
  104. Li, H.; Li, S.; Yu, B.; Liu, S. Expression of miR-133 and miR-30 in chronic atrial fibrillation in canines. Mol. Med. Rep. 2012, 5, 1457–1460. [Google Scholar] [PubMed]
  105. Duisters, R.F.; Tijsen, A.J.; Schroen, B.; Leenders, J.J.; Lentink, V.; van der Made, I.; Herias, V.; van Leeuwen, R.E.; Schellings, M.W.; Barenbrug, P.; et al. miR-133 and miR-30 regulate connective tissue growth factor: Implications for a role of microRNAs in myocardial matrix remodeling. Circ. Res. 2009, 104, 170–178. [Google Scholar] [CrossRef]
  106. Li, T.; Cao, H.; Zhuang, J.; Wan, J.; Guan, M.; Yu, B.; Li, X.; Zhang, W. Identification of miR-130a, miR-27b and miR-210 as serum biomarkers for atherosclerosis obliterans. Clin. Chim. Acta 2011, 412, 66–70. [Google Scholar] [CrossRef] [PubMed]
  107. Osbourne, A.; Calway, T.; Broman, M.; McSharry, S.; Earley, J.; Kim, G.H. Downregulation of connexin43 by microRNA-130a in cardiomyocytes results in cardiac arrhythmias. J. Mol. Cell. Cardiol. 2014, 74, 53–63. [Google Scholar] [CrossRef] [PubMed]
  108. Luo, X.; Zhang, H.; Xiao, J.; Wang, Z. Regulation of human cardiac ion channel genes by microRNAs: Theoretical perspective and pathophysiological implications. Cell. Physiol. Biochem. 2010, 25, 571–586. [Google Scholar] [CrossRef] [PubMed]
  109. Cha, M.J.; Jang, J.K.; Ham, O.; Song, B.W.; Lee, S.Y.; Lee, C.Y.; Park, J.H.; Lee, J.; Seo, H.H.; Choi, E.; et al. MicroRNA-145 suppresses ROS-induced Ca2+ overload of cardiomyocytes by targeting CaMKIIdelta. Biochem. Biophys. Res. Commun. 2013, 435, 720–726. [Google Scholar] [CrossRef]
  110. Li, C.; Li, X.; Gao, X.; Zhang, R.; Zhang, Y.; Liang, H.; Xu, C.; Du, W.; Zhang, Y.; Liu, X.; et al. MicroRNA-328 as a regulator of cardiac hypertrophy. Int. J. Cardiol. 2014, 173, 268–276. [Google Scholar] [CrossRef]
  111. Lu, Y.; Zhang, Y.; Wang, N.; Pan, Z.; Gao, X.; Zhang, F.; Zhang, Y.; Shan, H.; Luo, X.; Bai, Y.; et al. MicroRNA-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation 2010, 122, 2378–2387. [Google Scholar] [CrossRef] [PubMed]
  112. Ling, T.Y.; Wang, X.L.; Chai, Q.; Lau, T.W.; Koestler, C.M.; Park, S.J.; Daly, R.C.; Greason, K.L.; Jen, J.; Wu, L.Q.; et al. Regulation of the SK3 channel by microRNA-499—Potential role in atrial fibrillation. Heart Rhythm 2013, 10, 1001–1009. [Google Scholar] [CrossRef] [PubMed]
  113. Matkovich, S.J.; Hu, Y.; Eschenbacher, W.H.; Dorn, L.E.; Dorn, G.W., 2nd. Direct and indirect involvement of microRNA-499 in clinical and experimental cardiomyopathy. Circ. Res. 2012, 111, 521–531. [Google Scholar] [CrossRef] [PubMed]
  114. Li, X.; Wang, B.; Cui, H.; Du, Y.; Song, Y.; Yang, L.; Zhang, Q.; Sun, F.; Luo, D.; Xu, C.; et al. Let-7e replacement yields potent anti-arrhythmic efficacy via targeting beta 1-adrenergic receptor in rat heart. J. Cell. Mol. Med. 2014, 18, 1334–1343. [Google Scholar] [CrossRef] [PubMed]
  115. Zhou, M.; Cai, J.; Tang, Y.; Zhao, Q. MiR-17–92 cluster is a novel regulatory gene of cardiac ischemic/reperfusion injury. Med. Hypotheses 2013, 81, 108–110. [Google Scholar] [CrossRef] [PubMed]
  116. Bonauer, A.; Dimmeler, S. The microRNA-17-92 cluster: Still a miRacle? Cell Cycle 2009, 8, 3866–3873. [Google Scholar] [CrossRef] [PubMed]
  117. Oudit, G.Y.; Penninger, J.M. Cardiac regulation by phosphoinositide 3-kinases and PTEN. Cardiovasc. Res. 2009, 82, 250–260. [Google Scholar] [CrossRef]
  118. Thum, T.; Gross, C.; Fiedler, J.; Fischer, T.; Kissler, S.; Bussen, M.; Galuppo, P.; Just, S.; Rottbauer, W.; Frantz, S.; et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 2008, 456, 980–984. [Google Scholar] [CrossRef] [PubMed]
  119. Huebert, R.C.; Li, Q.; Adhikari, N.; Charles, N.J.; Han, X.; Ezzat, M.K.; Grindle, S.; Park, S.; Ormaza, S.; Fermin, D.; et al. Identification and regulation of Sprouty1, a negative inhibitor of the ERK cascade, in the human heart. Physiol. Genomics 2004, 18, 284–289. [Google Scholar] [CrossRef] [PubMed]
  120. Muda, M.; Theodosiou, A.; Rodrigues, N.; Boschert, U.; Camps, M.; Gillieron, C.; Davies, K.; Ashworth, A.; Arkinstall, S. The dual specificity phosphatases M3/6 and MKP-3 are highly selective for inactivation of distinct mitogen-activated protein kinases. J. Biol. Chem. 1996, 271, 27205–27208. [Google Scholar] [CrossRef] [PubMed]
  121. Liu, S.L.W.; Xu, M.; Huang, H.; Wang, J.; Chen, X. miR-21 Targets DUSP8 to promote collagen synthesis in high glucose treated primary cardiac fibroblasts. Can. J. Cardiol. 2014. [Google Scholar] [CrossRef]
  122. Van Rooij, E.; Sutherland, L.B.; Thatcher, J.E.; DiMaio, J.M.; Naseem, R.H.; Marshall, W.S.; Hill, J.A.; Olson, E.N. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc. Natl. Acad. Sci. USA 2008, 105, 13027–13032. [Google Scholar] [PubMed]
  123. Qu, Y.C.; Du, Y.M.; Wu, S.L.; Chen, Q.X.; Wu, H.L.; Zhou, S.F. Activated nuclear factor-kappaB and increased tumor necrosis factor-alpha in atrial tissue of atrial fibrillation. Scand. Cardiovasc. J. 2009, 43, 292–297. [Google Scholar] [CrossRef] [PubMed]
  124. Li, N.; Wang, T.; Wang, W.; Cutler, M.J.; Wang, Q.; Voigt, N.; Rosenbaum, D.S.; Dobrev, D.; Wehrens, X.H. Inhibition of CaMKII phosphorylation of RyR2 prevents induction of atrial fibrillation in FKBP12.6 knockout mice. Circ. Res. 2012, 110, 465–470. [Google Scholar] [CrossRef] [PubMed]
  125. McManus, D.D.; Lin, H.; Tanriverdi, K.; Quercio, M.; Yin, X.; Larson, M.G.; Ellinor, P.T.; Levy, D.; Freedman, J.E.; Benjamin, E.J. Relations between circulating microRNAs and atrial fibrillation: Data from the Framingham Offspring Study. Heart Rhythm 2014, 11, 663–669. [Google Scholar] [CrossRef] [PubMed]
  126. Chandy, K.G.; Fantino, E.; Wittekindt, O.; Kalman, K.; Tong, L.L.; Ho, T.H.; Gutman, G.A.; Crocq, M.A.; Ganguli, R.; Nimgaonkar, V.; et al. Isolation of a novel potassium channel gene hSKCa3 containing a polymorphic CAG repeat: A candidate for schizophrenia and bipolar disorder? Mol. Psychiatry 1998, 3, 32–37. [Google Scholar] [CrossRef] [PubMed]
  127. Wallukat, G. The beta-adrenergic receptors. Herz 2002, 27, 683–690. [Google Scholar] [CrossRef]
  128. Kuhlkamp, V.; Bosch, R.; Mewis, C.; Seipel, L. Use of beta-blockers in atrial fibrillation. Am. J. Cardiovasc. Drugs 2002, 2, 37–42. [Google Scholar] [CrossRef]
  129. Chen, T.; Ding, G.; Jin, Z.; Wagner, M.B.; Yuan, Z. Insulin ameliorates miR-1-induced injury in H9c2 cells under oxidative stress via Akt activation. Mol. Cell. Biochem. 2012, 369, 167–174. [Google Scholar] [CrossRef] [PubMed]
  130. Suh, J.H.; Choi, E.; Cha, M.J.; Song, B.W.; Ham, O.; Lee, S.Y.; Yoon, C.; Lee, C.Y.; Park, J.H.; Lee, S.H.; et al. Up-regulation of miR-26a promotes apoptosis of hypoxic rat neonatal cardiomyocytes by repressing GSK-3beta protein expression. Biochem. Biophys. Res. Commun. 2012, 423, 404–410. [Google Scholar] [CrossRef] [PubMed]
  131. Wang, J.; Jia, Z.; Zhang, C.; Sun, M.; Wang, W.; Chen, P.; Ma, K.; Zhang, Y.; Li, X.; Zhou, C. miR-499 protects cardiomyocytes from H2O2-induced apoptosis via its effects on Pdcd4 and Pacs2. RNA Biol. 2014, 11, 339–350. [Google Scholar] [CrossRef] [PubMed]
  132. Lin, Y.; Liu, X.; Cheng, Y.; Yang, J.; Huo, Y.; Zhang, C. Involvement of microRNAs in hydrogen peroxide-mediated gene regulation and cellular injury response in vascular smooth muscle cells. J. Biol. Chem. 2009, 284, 7903–7913. [Google Scholar] [CrossRef] [PubMed]
  133. Cheng, Y.; Liu, X.; Zhang, S.; Lin, Y.; Yang, J.; Zhang, C. MicroRNA-21 protects against the H2O2-induced injury on cardiac myocytes via its target gene PDCD4. J. Mol. Cell. Cardiol. 2009, 47, 5–14. [Google Scholar] [CrossRef] [PubMed]
  134. Li, J.; Donath, S.; Li, Y.; Qin, D.; Prabhakar, B.S.; Li, P. miR-30 regulates mitochondrial fission through targeting p53 and the dynamin-related protein-1 pathway. PLoS Genet. 2010, 6, e1000795. [Google Scholar] [CrossRef] [PubMed]
  135. Xu, C.; Hu, Y.; Hou, L.; Ju, J.; Li, X.; Du, N.; Guan, X.; Liu, Z.; Zhang, T.; Qin, W.; et al. Beta-Blocker carvedilol protects cardiomyocytes against oxidative stress-induced apoptosis by up-regulating miR-133 expression. J. Mol. Cell. Cardiol. 2014, 75, 111–121. [Google Scholar] [CrossRef] [PubMed]
  136. Li, R.; Yan, G.; Li, Q.; Sun, H.; Hu, Y.; Sun, J.; Xu, B. MicroRNA-145 protects cardiomyocytes against hydrogen peroxide (H2O2)-induced apoptosis through targeting the mitochondria apoptotic pathway. PLoS One 2012, 7, e44907. [Google Scholar] [CrossRef] [PubMed]
  137. Saleh, A.D.; Savage, J.E.; Cao, L.; Soule, B.P.; Ly, D.; DeGraff, W.; Harris, C.C.; Mitchell, J.B.; Simone, N.L. Cellular stress induced alterations in microRNA let-7a and let-7b expression are dependent on p53. PLoS One 2011, 6, e24429. [Google Scholar] [PubMed]
  138. Michel, J.B.; Li, Z.; Lacolley, P. Smooth muscle cells and vascular diseases. Cardiovasc. Res. 2012, 95, 135–137. [Google Scholar] [CrossRef] [PubMed]
  139. Agmon, Y.; Khandheria, B.K.; Meissner, I.; Schwartz, G.L.; Petterson, T.M.; O’Fallon, W.M.; Gentile, F.; Spittell, P.C.; Whisnant, J.P.; Wiebers, D.O.; et al. Association of atrial fibrillation and aortic atherosclerosis: A population-based study. Mayo Clin. Proc. 2001, 76, 252–259. [Google Scholar] [CrossRef] [PubMed]
  140. Willeit, K.; Pechlaner, R.; Egger, G.; Weger, S.; Oberhollenzer, M.; Willeit, J.; Kiechl, S. Carotid atherosclerosis and incident atrial fibrillation. Arterioscler. Thromb. Vasc. Biol. 2013, 33, 2660–2665. [Google Scholar] [CrossRef] [PubMed]
  141. Kulagina, N.V.; Michael, A.C. Monitoring hydrogen peroxide in the extracellular space of the brain with amperometric microsensors. Anal. Chem. 2003, 75, 4875–4881. [Google Scholar] [CrossRef] [PubMed]
  142. Tarpey, M.M.; Wink, D.A.; Grisham, M.B. Methods for detection of reactive metabolites of oxygen and nitrogen: In vitro and in vivo considerations. Am. J. Physiol. 2004, 286, R431–R444. [Google Scholar]
  143. Ozaydin, M. Atrial fibrillation and inflammation. World J. Cardiol. 2010, 2, 243–250. [Google Scholar] [CrossRef] [PubMed]
  144. Aldhoon, B.; Kucera, T.; Smorodinova, N.; Martinek, J.; Melenovsky, V.; Kautzner, J. Associations between cardiac fibrosis and permanent atrial fibrillation in advanced heart failure. Physiol. Res. 2013, 62, 247–255. [Google Scholar] [PubMed]
  145. Li, C.; Wang, F.; Yang, Y.; Fu, F.; Xu, C.; Shi, L.; Li, S.; Xia, Y.; Wu, G.; Cheng, X.; et al. Significant association of SNP rs2106261 in the ZFHX3 gene with atrial fibrillation in a Chinese Han GeneID population. Hum. Genet. 2011, 129, 239–246. [Google Scholar] [CrossRef] [PubMed]
  146. Heeringa, J.; Kors, J.A.; Hofman, A.; van Rooij, F.J.; Witteman, J.C. Cigarette smoking and risk of atrial fibrillation: The rotterdam study. Am. Heart J. 2008, 156, 1163–1169. [Google Scholar] [PubMed]
  147. Djousse, L.; Levy, D.; Benjamin, E.J.; Blease, S.J.; Russ, A.; Larson, M.G.; Massaro, J.M.; D’Agostino, R.B.; Wolf, P.A.; Ellison, R.C. Long-term alcohol consumption and the risk of atrial fibrillation in the framingham study. Am. J. Cardiol. 2004, 93, 710–713. [Google Scholar] [CrossRef] [PubMed]
  148. Gong, J.; Tong, Y.; Zhang, H.M.; Wang, K.; Hu, T.; Shan, G.; Sun, J.; Guo, A.Y. Genome-wide identification of SNPs in microRNA genes and the SNP effects on microRNA target binding and biogenesis. Hum. Mutat. 2012, 33, 254–263. [Google Scholar] [CrossRef] [PubMed]
  149. Su, Y.; Li, J.; Chen, F.; Geng, H.; Pan, M. A polymorphism rs11614913 in pre-microRNAs may be associated with atrial fibrillation in Han Chinese population. J. Am. Coll. Cardiol. 2014, 64, GW25-e0274. [Google Scholar] [CrossRef]
  150. Violi, F.; Loffredo, L. Thromboembolism or atherothromboembolism in atrial fibrillation? Circ. Arrhythm. Electrophysiol. 2012, 5, 1053–1055. [Google Scholar] [CrossRef] [PubMed]

Share and Cite

MDPI and ACS Style

Lee, S.; Choi, E.; Cha, M.-J.; Hwang, K.-C. Looking into a Conceptual Framework of ROS–miRNA–Atrial Fibrillation. Int. J. Mol. Sci. 2014, 15, 21754-21776. https://doi.org/10.3390/ijms151221754

AMA Style

Lee S, Choi E, Cha M-J, Hwang K-C. Looking into a Conceptual Framework of ROS–miRNA–Atrial Fibrillation. International Journal of Molecular Sciences. 2014; 15(12):21754-21776. https://doi.org/10.3390/ijms151221754

Chicago/Turabian Style

Lee, Seahyoung, Eunhyun Choi, Min-Ji Cha, and Ki-Chul Hwang. 2014. "Looking into a Conceptual Framework of ROS–miRNA–Atrial Fibrillation" International Journal of Molecular Sciences 15, no. 12: 21754-21776. https://doi.org/10.3390/ijms151221754

APA Style

Lee, S., Choi, E., Cha, M. -J., & Hwang, K. -C. (2014). Looking into a Conceptual Framework of ROS–miRNA–Atrial Fibrillation. International Journal of Molecular Sciences, 15(12), 21754-21776. https://doi.org/10.3390/ijms151221754

Article Metrics

Back to TopTop