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Revealing new landscape of cardiovascular disease through circular RNA-miRNA-mRNA axis
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Review
Revealing new landscape of cardiovascular disease through circular RNAmiRNA-mRNA axis ⁎
Qiang Su , Xiangwei Lv Department of Cardiology, the Affiliated Hospital of Guilin Medical University, China
A R T I C LE I N FO
A B S T R A C
Keyword: Cardiovascular diseases CircRNA MiRNA CeRNA
Non-coding RNA (ncRNA) is a kind of RNA, produced by genomic transcription and does not encode protein, but can regulate the function of genes, thus widely regulating pathological and physiological processes. The dynamic balance of the reticular structure between them is needed to regulate the homeostasis, the abnormal regulation of one of them may lead to the occurrence of the disease. CircRNA is mainly involved in the evolution of CVD through sponge-like regulation of miRNAs, subsequently regulating miRNAs and their targets, mRNA functions. The role of circRNA–miRNA–mRNA axis in pathogenesis of cardiovascular diseases has been recently reported and highlighted. In this review, the emerging roles of circRNA–miRNA–mRNA axis in cardiovascular pathophysiology and regulation were discussed, with a novel focus on cardioprotective network activities of the circRNA.
1. Introduction Cardiovascular disease (CVD) is a frequent cause to death, early and accurate diagnosis is of great benefit to reduce the mortality of CVD [1]. At present, rapid clinical progress and active research have been done in CVD research. Although great progress has been made in the diagnosis, treatment and prognosis of CVD in the past 20 years, novel therapeutic strategies based on mechanisms to protect the heart are still required [2]. Emerging evidence has indicated that genetic and epigenetic factors have an important impact on the progress of CVD. At present, ncRNA has attracted much research attention in the study of the mechanism of CVD and related abnormals [3–5]. In terms of length of nucleotides(nt), ncRNAs can divided into: tRNAs(74–95 nt), rRNAs (121–5000 nt), snRNAs(100–300 nt), snoRNAs(100–300 nt), gRNAs(55–70 nt), miRNAs(19–23 nt), piRNAs(24–30 nt), siRNAs (21–25 nt), lncRNAs (> 200 nt), and circRNAs (> 200 nt) [6]. In the past, it was generally believed that the low abundance of circRNA expression was probably misexpressed in splicing [7]. High throughput sequencing and novel calculation methods show that circRNA widely exists in eukaryotic transcriptome [8–10]. CircRNA, which is a covalent closed loop structure with neither 5′ to 3′ polarity nor polyadenosine (A) tail, is widely distributed in mammals, especially in humans and mice, and plays an important role in regulating gene expression and various cellular processes [10]. CircRNA is mainly distributed in cytoplasm and has a stable
⁎
and high expression in vivo. As circRNA is insensitive to nuclease, it is more stable than homologous linear RNA [11], which grants circRNA obvious advantages in the development and application of new clinical diagnostic markers and molecular-targeted therapy in cardiovascular diseases. In molecular biology, circRNA, such as lncRNA and mRNA, also contains a large number of miRNA binding sites. As a competitive endogenous RNA (ceRNA), circRNA regulates the expression of downstream target genes of miRNA by base complementary sponge adsorption miRNA [12]. MiRNA can reduce the stability of the mRNA or inhibit the translation of the messenger RNA by targeting its 3′-untranslated region (UTR), thereby negatively regulating the expression of the target gene. Diverse RNA transcripts including mRNAs; pseudogenes; lncRNA and circRNAs can competitively combine with the same miRNAs by microRNA response elements (MREs), removing or reducing the inhibition of genes targedted by the miRNAs and regulating the expression of the target genes. These RNA transcripts are called ceRNA, and such a new post-transcription regulation model is called ceRNA hypothesis [13]. CeRNA not only participates in the proliferation, differentiation and aging of normal cells, but also plays an important role in the pathogenesis of tumor and CVDs. RNAs can affect the pathogenesis of CVD at the transcriptional level via a large regulatory network of ceRNA [14,15]. Concerning important pathway, the novel pathological functions of these circRNA–miRNA–mRNA axes in CVDs have been expanded over the last 3 years, and new studies are gradually
Corresponding author at: Department of Cardiology, the Affiliated Hospital of Guilin Medical University, No. 15 Lequn Road, Guilin 541001, China. E-mail address: [email protected] (Q. Su).
https://doi.org/10.1016/j.ygeno.2019.10.006 Received 19 August 2019; Received in revised form 7 October 2019 0888-7543/ © 2019 Elsevier Inc. All rights reserved.
Please cite this article as: Qiang Su and Xiangwei Lv, Genomics, https://doi.org/10.1016/j.ygeno.2019.10.006
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List of abbreviation ncRNA circRNA miRNA siRNA CVD
ceRNA UTR MREs SATB2 HUVSMC HUVEC SP/KLF
Non-coding RNA circular RNA microRNA small interference RNA Cardiovascular disease
competitive endogenous RNA untranslated region microRNA response elements Special AT-rich binding protein-2 human vascular smooth muscle cells human vascular endothelial cells specialized protein/Kruppel-like transcription factor
sudden cardiac death. Thus, atherosclerosis is related to most death cases in cardiovascular diseases [19]. Zhang et al. was first construction and comprehensive analysis for dysregulated circRNA-associated competing endogenous RNA network in atherosclerosis, and found circRNAs might be prospective clinical markers in atherosclerosis [20]. Atherosclerosis has three pathogenesis, which are lipid infiltration theory, endothelial injury theory, vascular smooth muscle cell migration and diffusion theory [21]. The circRNA termed special AT-rich binding protein-2 (SATB2) inhibit the proliferation and migration of vascular smooth muscle cells through circ-SATB2-mir-939–STIM1(stromal interaction molecule 1) axis. Overexpression of circ-SATB2 can induce apoptosis, and the binding of circ-SATB2 to mir-939 decreases the activity of mir-939, thus upregulating the target gene STIM1, and eventually aggravating the development of atherosclerosis [22]. A similar study found that circRNA-0044073 promoted the proliferation of human vascular smooth muscle cells through the circRNA-0044073mir-107–JAK/STAT axis. The overexpression of circRNA-0044073 promoted the proliferation of human vascular smooth muscle cells (HUVSMC) and human vascular endothelial cells (HUVEC), which could be inhibited by the overexpression of miR-107. In addition, circRNA-0044073 inhibited the level of miR-107 through sponge mechanism. Overexpression of circRNA-0044073 activates JAK/STAT signal transduction pathway and inflammation in HUVSMC and HUVEC [23]. The miR-221 is a decrease abundant and conserved imprinted gene reported in carotid plaque rupture [24]. However, the function of mir-221 in carotid plaque rupture is unknown. It was shown that circR284 sponging mir-221 axis was involved in promotion of carotid plaque rupture [25]. Simultaneously, Sun et al. found circ_RUSC2 upregulates the expression of miR-661 target gene SYK and regulates the function of vascular smooth muscle cells [26].
revealing their unique mechanisms in CVDs and abnormal cardiovascular conditions(Table 1). Therefore, the study of circRNA–miRNA–mRNA axes may provide a new direction for pathogenesis, diagnosis and treatment of CVD. 2. CircRNA–miRNA–mRNA axes in CVD 2.1. Coronary heart diseas Coronary heart disease(CHD) is the highest mortality rate among CVD. It is valued by clinicians, but there are certain difficulties in early diagnosis [16]. There are many ways to diagnose at present. Non-invasive examinations include electrocardiogram (ECG), electrocardiogram tread motion test (TET), Holter monitoring and coronary computed tomography (CTA), and invasive coronary angiography (CAG). However, each has its drawbacks, ECG sensitivity and specificity are low, CTA is expensive, and patients are generally difficult to accept CAG. The special ring structure of circRNA is not easily decomposed by enzymes, which proves that it can be used as a method for diagnosing CHD. Lin et al. and Pan et al. construct and comprehensive analysis for dysregulated circRNA-associated competing endogenous RNA network in coronary heart disease, and found circRNAs might be prospective clinical markers in the CHD [17,18]. 2.2. Atherosclerosi Atherosclerosis, which is a common pathological basis to many cardiovascular diseases, is caused by the accumulation of fat deposits, inflammatory reactions, cells and scar tissue in the arterial wall, and the disease can lead to stenosis and occlusion of the arterial lumen, causing ischemic necrosis of tissues and organs, angina pectoris and even Table 1 Associated circRNA–miRNA-mRNA axes in cardiovascular diseases. Diseases
CircRNA
MiRNA
Target gene(s)
Mechanism(s)
Ref.
Atherosclerosis
Circ-SATB2
mir-939
STIM1
[22]
CircRNA-0044073 CircR-284 Circ_RUSC2 CircRNA cdr1as MFACR Circ-Ttc3 Circ_Nfix HRCR CircRNA_000203
JAK/STAT NR SYK PARP, SP1 MTP18 Arl2 Ybx1 ARC gata4
CircSlc8a1 CircRNA_010567 CircHIPK3
mir-107 mir-221 mir-661 mir-7a miR-652-3p miR-15b miR-214 mir-223 miR26b-5p/miR-1403p miR-133a mir-141 miR-29b-3p
inhibit the proliferation and migration of vascular smooth muscle cells promoted the proliferation of human vascular smooth muscle cells plaque rupture promoted the proliferation of human vascular smooth muscle cells induce apoptosis induce cardiomyocyte apoptosis induce apoptosis promotes cardiac regenerative repair and functional recovery induce apoptosis aggravates cardiac hypertrophy attenuates pressure overload promotes the expression of fibronectin attenuates cardiac fibroblasts proliferation, migration
[41] [44] [45]
CircNFIB CircRNA_000203 circ_0076631 Circ-000595 Circ-ncx1 Circ ACR
miR-433 mirRNA-26p-5p miR-214-3p mir-19a miR-133a-3p NR
promote proliferation and differentiation of cardiac fibroblasts anti-fibrosis suppressing cardiomyocyte inflammation and death induce the apoptosis of smooth muscle cells promotes the cardiomyocyte apoptosis attenuates autophagy and cell death
[46] [49] [50] [53] [55] [56]
Myocardial infarction
Cardiac hypertrophy
Cardiac fibrosis
Diabetic cardiomyopathy Aortic aneurysm Ischemic heart disease
NR TGF-β1 a-SMA, COL1A1, COL3A1 AZIN1/JNK1 Colla2, CTGF caspase-1 NR CDIP1 FAM65B
NR: Not reported directly. 2
[23] [25] [26] [30] 33 [34] [35] [39] [40]
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Biological stress and other pathological stimuli can lead to myocardial remodeling. The heart responds to these stimuli without affecting function, manifesting as cardiac hypertrophy, myocardial cell enlargement and extracardiac fiber formation, but no changes in the number of cardiomyocytes. This adaptation mechanism is beneficial in a short term, however, a long-term response to cardiac hypertrophy caused by stimulation may lead to heart failure and even sudden death [38]. The circRNA termed heart-related circRNA (HRCR) inhibit cardiac hypertrophy and heart failure through the HRCR-mir-223–ARC(inhibitor of apoptosis with CARD) axis. Studies have shown that mir223 transgenic mice are tended to develop myocardial hypertrophy and heart failure, while mir-223 knockout mice do not have these lesions, which proves that miR-223 is a positive regulator of heart failure. The ARC(inhibitor of apoptosis with CARD), which contains cytosolic peptidase enrichment domain is a downstream anti-apoptosis protein regulated by miR-223. HRCR adsorbs mir-223 through sponge to eliminate the inhibitory effect of mir-223 on the expression of ARC protein, and then increases the expression of ARC protein in cardiomyocytes and mice [39]. Therefore, the overexpression of circRNA HRCR can inhibit heart failure. Furthermore, Li et al. found circRNA_000203 exacerbates cardiac hypertrophy via suppressing miR26b-5p and miR-140-3p leading to enhanced Gata4 levels [40]. In addition, Lim et al. found circSlc8a1 is up-regulated in the heart, and canattenuates pressure overload induced hypertrophy by sponging miR133a [41]. This finding provides a new therapeutic target for the treatment of cardiac hypertrophy.
2.3. Myocardial infarctio Myocardial infarction and its complications create economic burden to social and health care system. Although a large number of studies have shown that cardiac stem cells can improve cardiac function after transplantation of ischemic heart, its treatment of myocardial infarction is still in its infancy [27,28]. Therefore, it is important to study the mechanism of myocardial infarction and discover effective treatment strategies. Myocardial hypertrophy, cardiomyocyte apoptosis, cardiomyocyte metabolism and myocardial fibrosis are pathological changes after myocardial infarction, however, the mechanism of such a development is still unclear. During myocardial infarction, oxidative stress and insufficient myocardial blood supply will lead to insufficient oxygen supply, resulting in irreversible damage to myocardial cells. In addition to the direct biological response, myocardial cell death releases toxic substances that trigger left ventricular remodeling, leading to functional decomposition and heart failure [28]. Jiang et al. was first construction and comprehensive analysis for dysregulated circRNA-associated competing endogenous RNA network in atrial fibrillation [29]. The circRNA termed cerebellar degeneration-related protein 1 transcript (Cdr1as) promoted cell apoptosis through the circRNA cdr1asmir-7a–PARP(poly ADP-ribose polymerase) or SP1 (specialized protein 1) axis. Overexpression of circRNA cdr1as could induce apoptosis, and cdr1as combined with miR-7a decreased the activity of miR-7a, thus upregulating miR-7a target gene PARP and SP1, and eventually aggravating the development of myocardial infarction [30]. SP1, a member of the transcription factor specialized protein/Kruppel-like transcription factor (SP/KLF) family [31], has been shown to be involved in the occurrence and development of myocardial infarction including myocardial fibrosis, apoptosis and vascular regeneration, play an important role, and PARP has a similar function. However, the overexpression of miR-7a can significantly inhibit the changes induced by Cdr1as and thus protect the apoptosis induced by myocardial infarction [32]. Therefore, cdr1as-7-miR-7-PARP/SP1 axis can provide a new biomarker for the early diagnosis of myocardial infarction, and its expression level is closely related to the prognosis of patients. It has been reported that MFACR (mitochondrial fission and apoptosis-related circRNA) was significantly up-regulated in the rat model of cardiomyocyte apoptosis induced by coronary artery ligation, and the MFACR promoted the cardiac mitochondrial division and apoptosis through the MFACR-miR-652-3p–MTP18 (mitochondrial protein 18) axis. MiRNA652-3p can block mitochondrial cleavage and cardiomyocyte death by inhibiting the expression of MTP18. MFACR directly chelates miR-6523p in cytoplasm and inhibits its activity [33]. Furthermore, circ-Ttc3 represents one of the top highest expressed circRNAs in the heart, Cai et al. found circ-Ttc3 regulates cardiac function after myocardial infarction by sponging miR-15b-Arl2 [34]. In addition, Huang et al. found circRNA Nfix promotes cardiomyocyte proliferation and angiogenesis by suppressing Ybx1 (Y-box binding protein 1) ubiquitin-dependent degradation and rescuing miR-214 [35]. The findings of MFACR, circRNA_cdr1as, circ-Ttc3 and circRNA Nfix provide a new basis to further study of the occurrence and subsequent diagnosis and treatment of myocardial infarction. CircRNA plays a key role in the regulation of cardiac mitochondrial kinetics and apoptosis, and the discovery of circRNA Cdr1 and MFACR provides a new basis for the further study of myocardial infarction.
2.5. Cardiac fibrosi Myocardial fibrosis refers to a variety of quantitative and qualitative changes in the interstitial myocardial collagen network, which occur in response to ischemic cardiac injury, systemic diseases, drugs, or any other harmful stimuli affecting the circulatory system or the heart itself. Myocardial fibrosis is a common type of cardiac tissue degeneration caused by hyperfunction of fibroblasts and differentiation into myofibroblasts. In a long run, if excess extracellular matrix is secreted and accumulated in the heart muscle, the pressure caused by hard fibrous tissue will lead to cardiac remodeling. Myocardial fibrosis changes the structure of myocardium, promotes the development of cardiac dysfunction, and induces arrhythmias, which affects the clinical process and results of patients with heart failure [42,43]. CircRNA_010567 can promote myocardial fibrosis through the circRNA_010567-mir-141–TGF-β1 axis. The team who first analyzed circRNA in the myocardium of diabetic db/db mice using chip method found that circRNA_010567 was significantly up-regulated in angiotensin II (Ang II) treated myocardium and cardiac fibroblasts. Then informatics analysis found that circRNA_010567 could competitively bind to mir-141, and confirmed the prediction results by luciferase reporter gene test. Knocking out circRNA-010567 can increase miR-141 increased and downregulate transforming growth factor β 1 (TGF- β1), and then inhibits the expressions of fibrosis-associated proteins Col I, CO II and α-SMA [44]. In conclusion, circRNA_010567 promotes the expression of fibronectin through miR-141/TGF- β 1 axis, which in turn promotes myocardial fibrosis. Such findings provide a new vision for the study of circRNA in cardiovascular diseases. Furthermore, Ni et al. found circHIPK3 expression markedly increased in CFs and heart tissues after the treatment of Ang II, and Inhibition of circHIPK3 prevents angiotensin II-induced cardiac fibrosis by sponging miR-29b-3p [45]. In addition, Zhu et al. found circNFIB is downregulated in cardiac fibrosis in vivo and in vitro, and upregulation of circNFIB attenuates cardiac fibrosis by sponging miR-433 [46].
2.4. Cardiac hypertroph Heart failure is one of the leading causes to death worldwide, and there is a close link between cardiac hypertrophy and heart failure. Cardiac hypertrophy is highly possible to eventually develops into heart failure. It is believed that there are many factors affecting cardiac function and participating in myocardial hypertrophy, such as G protein coupled receptors, epinephrine and angiotensin [36,37].
2.6. Diabetic cardiomyopath Diabetic patients have a significantly increased risk of developing diabetic cardiomyopathy [47,48]. CircRNA_000203 was shown 3
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upregulated in the diabetic mouse myocardium and in Ang-II-induced mouse cardiac fibroblasts. CircRNA_000203 contains two sites that bind to mirRNA-26p-5p, and mirRNA-26p-5p can play an anti-fibrosis role by binding to Colla2 and CTGF. Overexpression of circRNA_000203 can decrease the anti-fibrosis effect of mir-26p-5p in myocardial fibrosis. In addition, blocking miR-26p-5p could produce protective effect on myocardial fibrosis consistent with overexpression of circRNA_000203. Therefore, the circRNA_000203 can play an anti-fibrosis through the circRNA_000203-mirRNA-26p-5p–Colla2 or CTGF axis [49]. Furthermore, Yang et al. found circ_0076631 was increased both in high-glucose-treated cardiomyocytes and in the serum of diabetic patients, and can sponged an endogenous miR-214-3p/caspase-1 to sequester and inhibit its expression [50].
oxygen consumption, as well as to myocardial apoptosis, necrosis and fibrosis in ischemic site. Studies have found that circRNA was associated with myocardial cell regeneration and vascular regeneration in ischemic heart disease [54]. The circRNA termed sodium/calcium exchanger 1 (ncx1) promotes the cardiomyocyte apoptosis through the circ-ncx1-miR-133a-3p–CDIP1(cell death-inducing protein) axis. Overexpression of circ-ncx1 can promotes the cardiomyocyte apoptosis, and the binding of circ-ncx1 to miR-133a-3p decreases the activity of miR133a-3p, thus upregulating the target gene CDIP1, and eventually aggravating the development of ischemic heart disease [55]. Furthermore, Zhou et al. found circRNA ACR attenuates myocardial ischemia/reperfusion injury by suppressing autophagy via modulation of the Pink1/ FAM65B pathway [56].
2.7. Aortic aneurys
3. Conclusion and future perspectiv
Aortic aneurysm, which refers to the pathological dilatation of aorta, and it also has a high risk of death and the mechanism is complex [51,52]. Research reported that hsa-circ-000595 is associated with apoptosis of aortic smooth muscle, which in turn affects the occurrence of aortic aneurysms. The expression of hsa-circ-000595 in aortic smooth muscle cells was up-regulated under hypoxic conditions. The apoptosis of aortic smooth muscle cells was decreased by knockdown of hsa-circ000595. It was also found that hsa-circ-000595 acted as the cavernous body of mir-19a, and the decrease of hsacirc-000595 could increase the expression of mir-19a and reduce the apoptosis of smooth muscle cells [53]. Though the mechanism of miR-19a affecting smooth muscle cells needs to be further explored, the discovery of hsa-circ-000595 could provide a new genetic basis to the diagnosis and treatment of aortic aneurysms.
To the best of our knowledge, this is the most comprehensive review to explore the current knowledge concerning circRNA–miRNA–mRNA axis in the pathogenesis and development of CVDs and abnormal conditions(Fig. 1). CircRNA, as a newly discovered molecule with special biological function, has good specificity and stability. Its potential as a biomarker has been proved in cardiovascular diseases. Cardiovascular disease is a kind of disease with high morbidity and mortality. The mechanism of its occurrence and development is not clear. Revealing the occurrence and development of cardiovascular disease at the molecular level will provide a more efficient and accurate method for its early diagnosis, treatment and prognosis of the disease. The study on the role of cyclic RNA in cardiovascular diseases has revealed a new angle, which provides a new idea for the diagnosis and prognosis of cardiovascular diseases. Although circRNAs have increasingly been found to be differentially expressed between diseased cardiovascular tissues and normal tissues, the role of circRNA in cellular and molecular mechanisms were partly known. At present, only a few circRNAs, such as HRCR and circRNA Cdr1as have been proved to be related to cardiovascular diseases, most
2.8. Ischemic heart diseas Ischemic heart disease is a kind of coronary artery stenosis, which leads to the imbalance between coronary blood flow and myocardial
Fig. 1. CircRNAs function as ceRNAs in cardiovascular diseases. Red lines represent promotion, black lines represent suppression. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) 4
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of which play a role as the cavernous body of miRNA, suggesting that there may be some relationship between the two. CircRNA-miRNA targeting mRNA can not only be used as a promising biomarker for early diagnosis and stratification, but also as an advanced molecular technology to simulate or manufacture therapeutic agents. [17]
Authors' contributions
[18]
Qiang Su designed the research and wrote the paper; Qiang Su and Xiangwei Lv interpreted the data. All authors read and approved the final manuscript.
[19] [20]
Fundin This work was received National Natural Science Foundation of China (Grant No. 81600283) and Guangxi Natural Science Foundation (Grant No. 2017GXNSFAA198069).
[21] [22]
Declaration of Competing Interest
[23]
The authors declare that they have no competing interests.
[24]
Acknowledgement [25]
Not applicable. [26]
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Genomics journal homepage: www.elsevier.com/locate/ygeno
Review
Revealing new landscape of cardiovascular disease through circular RNAmiRNA-mRNA axis ⁎
Qiang Su , Xiangwei Lv Department of Cardiology, the Affiliated Hospital of Guilin Medical University, China
A R T I C LE I N FO
A B S T R A C
Keyword: Cardiovascular diseases CircRNA MiRNA CeRNA
Non-coding RNA (ncRNA) is a kind of RNA, produced by genomic transcription and does not encode protein, but can regulate the function of genes, thus widely regulating pathological and physiological processes. The dynamic balance of the reticular structure between them is needed to regulate the homeostasis, the abnormal regulation of one of them may lead to the occurrence of the disease. CircRNA is mainly involved in the evolution of CVD through sponge-like regulation of miRNAs, subsequently regulating miRNAs and their targets, mRNA functions. The role of circRNA–miRNA–mRNA axis in pathogenesis of cardiovascular diseases has been recently reported and highlighted. In this review, the emerging roles of circRNA–miRNA–mRNA axis in cardiovascular pathophysiology and regulation were discussed, with a novel focus on cardioprotective network activities of the circRNA.
1. Introduction Cardiovascular disease (CVD) is a frequent cause to death, early and accurate diagnosis is of great benefit to reduce the mortality of CVD [1]. At present, rapid clinical progress and active research have been done in CVD research. Although great progress has been made in the diagnosis, treatment and prognosis of CVD in the past 20 years, novel therapeutic strategies based on mechanisms to protect the heart are still required [2]. Emerging evidence has indicated that genetic and epigenetic factors have an important impact on the progress of CVD. At present, ncRNA has attracted much research attention in the study of the mechanism of CVD and related abnormals [3–5]. In terms of length of nucleotides(nt), ncRNAs can divided into: tRNAs(74–95 nt), rRNAs (121–5000 nt), snRNAs(100–300 nt), snoRNAs(100–300 nt), gRNAs(55–70 nt), miRNAs(19–23 nt), piRNAs(24–30 nt), siRNAs (21–25 nt), lncRNAs (> 200 nt), and circRNAs (> 200 nt) [6]. In the past, it was generally believed that the low abundance of circRNA expression was probably misexpressed in splicing [7]. High throughput sequencing and novel calculation methods show that circRNA widely exists in eukaryotic transcriptome [8–10]. CircRNA, which is a covalent closed loop structure with neither 5′ to 3′ polarity nor polyadenosine (A) tail, is widely distributed in mammals, especially in humans and mice, and plays an important role in regulating gene expression and various cellular processes [10]. CircRNA is mainly distributed in cytoplasm and has a stable
⁎
and high expression in vivo. As circRNA is insensitive to nuclease, it is more stable than homologous linear RNA [11], which grants circRNA obvious advantages in the development and application of new clinical diagnostic markers and molecular-targeted therapy in cardiovascular diseases. In molecular biology, circRNA, such as lncRNA and mRNA, also contains a large number of miRNA binding sites. As a competitive endogenous RNA (ceRNA), circRNA regulates the expression of downstream target genes of miRNA by base complementary sponge adsorption miRNA [12]. MiRNA can reduce the stability of the mRNA or inhibit the translation of the messenger RNA by targeting its 3′-untranslated region (UTR), thereby negatively regulating the expression of the target gene. Diverse RNA transcripts including mRNAs; pseudogenes; lncRNA and circRNAs can competitively combine with the same miRNAs by microRNA response elements (MREs), removing or reducing the inhibition of genes targedted by the miRNAs and regulating the expression of the target genes. These RNA transcripts are called ceRNA, and such a new post-transcription regulation model is called ceRNA hypothesis [13]. CeRNA not only participates in the proliferation, differentiation and aging of normal cells, but also plays an important role in the pathogenesis of tumor and CVDs. RNAs can affect the pathogenesis of CVD at the transcriptional level via a large regulatory network of ceRNA [14,15]. Concerning important pathway, the novel pathological functions of these circRNA–miRNA–mRNA axes in CVDs have been expanded over the last 3 years, and new studies are gradually
Corresponding author at: Department of Cardiology, the Affiliated Hospital of Guilin Medical University, No. 15 Lequn Road, Guilin 541001, China. E-mail address: [email protected] (Q. Su).
https://doi.org/10.1016/j.ygeno.2019.10.006 Received 19 August 2019; Received in revised form 7 October 2019 0888-7543/ © 2019 Elsevier Inc. All rights reserved.
Please cite this article as: Qiang Su and Xiangwei Lv, Genomics, https://doi.org/10.1016/j.ygeno.2019.10.006
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List of abbreviation ncRNA circRNA miRNA siRNA CVD
ceRNA UTR MREs SATB2 HUVSMC HUVEC SP/KLF
Non-coding RNA circular RNA microRNA small interference RNA Cardiovascular disease
competitive endogenous RNA untranslated region microRNA response elements Special AT-rich binding protein-2 human vascular smooth muscle cells human vascular endothelial cells specialized protein/Kruppel-like transcription factor
sudden cardiac death. Thus, atherosclerosis is related to most death cases in cardiovascular diseases [19]. Zhang et al. was first construction and comprehensive analysis for dysregulated circRNA-associated competing endogenous RNA network in atherosclerosis, and found circRNAs might be prospective clinical markers in atherosclerosis [20]. Atherosclerosis has three pathogenesis, which are lipid infiltration theory, endothelial injury theory, vascular smooth muscle cell migration and diffusion theory [21]. The circRNA termed special AT-rich binding protein-2 (SATB2) inhibit the proliferation and migration of vascular smooth muscle cells through circ-SATB2-mir-939–STIM1(stromal interaction molecule 1) axis. Overexpression of circ-SATB2 can induce apoptosis, and the binding of circ-SATB2 to mir-939 decreases the activity of mir-939, thus upregulating the target gene STIM1, and eventually aggravating the development of atherosclerosis [22]. A similar study found that circRNA-0044073 promoted the proliferation of human vascular smooth muscle cells through the circRNA-0044073mir-107–JAK/STAT axis. The overexpression of circRNA-0044073 promoted the proliferation of human vascular smooth muscle cells (HUVSMC) and human vascular endothelial cells (HUVEC), which could be inhibited by the overexpression of miR-107. In addition, circRNA-0044073 inhibited the level of miR-107 through sponge mechanism. Overexpression of circRNA-0044073 activates JAK/STAT signal transduction pathway and inflammation in HUVSMC and HUVEC [23]. The miR-221 is a decrease abundant and conserved imprinted gene reported in carotid plaque rupture [24]. However, the function of mir-221 in carotid plaque rupture is unknown. It was shown that circR284 sponging mir-221 axis was involved in promotion of carotid plaque rupture [25]. Simultaneously, Sun et al. found circ_RUSC2 upregulates the expression of miR-661 target gene SYK and regulates the function of vascular smooth muscle cells [26].
revealing their unique mechanisms in CVDs and abnormal cardiovascular conditions(Table 1). Therefore, the study of circRNA–miRNA–mRNA axes may provide a new direction for pathogenesis, diagnosis and treatment of CVD. 2. CircRNA–miRNA–mRNA axes in CVD 2.1. Coronary heart diseas Coronary heart disease(CHD) is the highest mortality rate among CVD. It is valued by clinicians, but there are certain difficulties in early diagnosis [16]. There are many ways to diagnose at present. Non-invasive examinations include electrocardiogram (ECG), electrocardiogram tread motion test (TET), Holter monitoring and coronary computed tomography (CTA), and invasive coronary angiography (CAG). However, each has its drawbacks, ECG sensitivity and specificity are low, CTA is expensive, and patients are generally difficult to accept CAG. The special ring structure of circRNA is not easily decomposed by enzymes, which proves that it can be used as a method for diagnosing CHD. Lin et al. and Pan et al. construct and comprehensive analysis for dysregulated circRNA-associated competing endogenous RNA network in coronary heart disease, and found circRNAs might be prospective clinical markers in the CHD [17,18]. 2.2. Atherosclerosi Atherosclerosis, which is a common pathological basis to many cardiovascular diseases, is caused by the accumulation of fat deposits, inflammatory reactions, cells and scar tissue in the arterial wall, and the disease can lead to stenosis and occlusion of the arterial lumen, causing ischemic necrosis of tissues and organs, angina pectoris and even Table 1 Associated circRNA–miRNA-mRNA axes in cardiovascular diseases. Diseases
CircRNA
MiRNA
Target gene(s)
Mechanism(s)
Ref.
Atherosclerosis
Circ-SATB2
mir-939
STIM1
[22]
CircRNA-0044073 CircR-284 Circ_RUSC2 CircRNA cdr1as MFACR Circ-Ttc3 Circ_Nfix HRCR CircRNA_000203
JAK/STAT NR SYK PARP, SP1 MTP18 Arl2 Ybx1 ARC gata4
CircSlc8a1 CircRNA_010567 CircHIPK3
mir-107 mir-221 mir-661 mir-7a miR-652-3p miR-15b miR-214 mir-223 miR26b-5p/miR-1403p miR-133a mir-141 miR-29b-3p
inhibit the proliferation and migration of vascular smooth muscle cells promoted the proliferation of human vascular smooth muscle cells plaque rupture promoted the proliferation of human vascular smooth muscle cells induce apoptosis induce cardiomyocyte apoptosis induce apoptosis promotes cardiac regenerative repair and functional recovery induce apoptosis aggravates cardiac hypertrophy attenuates pressure overload promotes the expression of fibronectin attenuates cardiac fibroblasts proliferation, migration
[41] [44] [45]
CircNFIB CircRNA_000203 circ_0076631 Circ-000595 Circ-ncx1 Circ ACR
miR-433 mirRNA-26p-5p miR-214-3p mir-19a miR-133a-3p NR
promote proliferation and differentiation of cardiac fibroblasts anti-fibrosis suppressing cardiomyocyte inflammation and death induce the apoptosis of smooth muscle cells promotes the cardiomyocyte apoptosis attenuates autophagy and cell death
[46] [49] [50] [53] [55] [56]
Myocardial infarction
Cardiac hypertrophy
Cardiac fibrosis
Diabetic cardiomyopathy Aortic aneurysm Ischemic heart disease
NR TGF-β1 a-SMA, COL1A1, COL3A1 AZIN1/JNK1 Colla2, CTGF caspase-1 NR CDIP1 FAM65B
NR: Not reported directly. 2
[23] [25] [26] [30] 33 [34] [35] [39] [40]
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Biological stress and other pathological stimuli can lead to myocardial remodeling. The heart responds to these stimuli without affecting function, manifesting as cardiac hypertrophy, myocardial cell enlargement and extracardiac fiber formation, but no changes in the number of cardiomyocytes. This adaptation mechanism is beneficial in a short term, however, a long-term response to cardiac hypertrophy caused by stimulation may lead to heart failure and even sudden death [38]. The circRNA termed heart-related circRNA (HRCR) inhibit cardiac hypertrophy and heart failure through the HRCR-mir-223–ARC(inhibitor of apoptosis with CARD) axis. Studies have shown that mir223 transgenic mice are tended to develop myocardial hypertrophy and heart failure, while mir-223 knockout mice do not have these lesions, which proves that miR-223 is a positive regulator of heart failure. The ARC(inhibitor of apoptosis with CARD), which contains cytosolic peptidase enrichment domain is a downstream anti-apoptosis protein regulated by miR-223. HRCR adsorbs mir-223 through sponge to eliminate the inhibitory effect of mir-223 on the expression of ARC protein, and then increases the expression of ARC protein in cardiomyocytes and mice [39]. Therefore, the overexpression of circRNA HRCR can inhibit heart failure. Furthermore, Li et al. found circRNA_000203 exacerbates cardiac hypertrophy via suppressing miR26b-5p and miR-140-3p leading to enhanced Gata4 levels [40]. In addition, Lim et al. found circSlc8a1 is up-regulated in the heart, and canattenuates pressure overload induced hypertrophy by sponging miR133a [41]. This finding provides a new therapeutic target for the treatment of cardiac hypertrophy.
2.3. Myocardial infarctio Myocardial infarction and its complications create economic burden to social and health care system. Although a large number of studies have shown that cardiac stem cells can improve cardiac function after transplantation of ischemic heart, its treatment of myocardial infarction is still in its infancy [27,28]. Therefore, it is important to study the mechanism of myocardial infarction and discover effective treatment strategies. Myocardial hypertrophy, cardiomyocyte apoptosis, cardiomyocyte metabolism and myocardial fibrosis are pathological changes after myocardial infarction, however, the mechanism of such a development is still unclear. During myocardial infarction, oxidative stress and insufficient myocardial blood supply will lead to insufficient oxygen supply, resulting in irreversible damage to myocardial cells. In addition to the direct biological response, myocardial cell death releases toxic substances that trigger left ventricular remodeling, leading to functional decomposition and heart failure [28]. Jiang et al. was first construction and comprehensive analysis for dysregulated circRNA-associated competing endogenous RNA network in atrial fibrillation [29]. The circRNA termed cerebellar degeneration-related protein 1 transcript (Cdr1as) promoted cell apoptosis through the circRNA cdr1asmir-7a–PARP(poly ADP-ribose polymerase) or SP1 (specialized protein 1) axis. Overexpression of circRNA cdr1as could induce apoptosis, and cdr1as combined with miR-7a decreased the activity of miR-7a, thus upregulating miR-7a target gene PARP and SP1, and eventually aggravating the development of myocardial infarction [30]. SP1, a member of the transcription factor specialized protein/Kruppel-like transcription factor (SP/KLF) family [31], has been shown to be involved in the occurrence and development of myocardial infarction including myocardial fibrosis, apoptosis and vascular regeneration, play an important role, and PARP has a similar function. However, the overexpression of miR-7a can significantly inhibit the changes induced by Cdr1as and thus protect the apoptosis induced by myocardial infarction [32]. Therefore, cdr1as-7-miR-7-PARP/SP1 axis can provide a new biomarker for the early diagnosis of myocardial infarction, and its expression level is closely related to the prognosis of patients. It has been reported that MFACR (mitochondrial fission and apoptosis-related circRNA) was significantly up-regulated in the rat model of cardiomyocyte apoptosis induced by coronary artery ligation, and the MFACR promoted the cardiac mitochondrial division and apoptosis through the MFACR-miR-652-3p–MTP18 (mitochondrial protein 18) axis. MiRNA652-3p can block mitochondrial cleavage and cardiomyocyte death by inhibiting the expression of MTP18. MFACR directly chelates miR-6523p in cytoplasm and inhibits its activity [33]. Furthermore, circ-Ttc3 represents one of the top highest expressed circRNAs in the heart, Cai et al. found circ-Ttc3 regulates cardiac function after myocardial infarction by sponging miR-15b-Arl2 [34]. In addition, Huang et al. found circRNA Nfix promotes cardiomyocyte proliferation and angiogenesis by suppressing Ybx1 (Y-box binding protein 1) ubiquitin-dependent degradation and rescuing miR-214 [35]. The findings of MFACR, circRNA_cdr1as, circ-Ttc3 and circRNA Nfix provide a new basis to further study of the occurrence and subsequent diagnosis and treatment of myocardial infarction. CircRNA plays a key role in the regulation of cardiac mitochondrial kinetics and apoptosis, and the discovery of circRNA Cdr1 and MFACR provides a new basis for the further study of myocardial infarction.
2.5. Cardiac fibrosi Myocardial fibrosis refers to a variety of quantitative and qualitative changes in the interstitial myocardial collagen network, which occur in response to ischemic cardiac injury, systemic diseases, drugs, or any other harmful stimuli affecting the circulatory system or the heart itself. Myocardial fibrosis is a common type of cardiac tissue degeneration caused by hyperfunction of fibroblasts and differentiation into myofibroblasts. In a long run, if excess extracellular matrix is secreted and accumulated in the heart muscle, the pressure caused by hard fibrous tissue will lead to cardiac remodeling. Myocardial fibrosis changes the structure of myocardium, promotes the development of cardiac dysfunction, and induces arrhythmias, which affects the clinical process and results of patients with heart failure [42,43]. CircRNA_010567 can promote myocardial fibrosis through the circRNA_010567-mir-141–TGF-β1 axis. The team who first analyzed circRNA in the myocardium of diabetic db/db mice using chip method found that circRNA_010567 was significantly up-regulated in angiotensin II (Ang II) treated myocardium and cardiac fibroblasts. Then informatics analysis found that circRNA_010567 could competitively bind to mir-141, and confirmed the prediction results by luciferase reporter gene test. Knocking out circRNA-010567 can increase miR-141 increased and downregulate transforming growth factor β 1 (TGF- β1), and then inhibits the expressions of fibrosis-associated proteins Col I, CO II and α-SMA [44]. In conclusion, circRNA_010567 promotes the expression of fibronectin through miR-141/TGF- β 1 axis, which in turn promotes myocardial fibrosis. Such findings provide a new vision for the study of circRNA in cardiovascular diseases. Furthermore, Ni et al. found circHIPK3 expression markedly increased in CFs and heart tissues after the treatment of Ang II, and Inhibition of circHIPK3 prevents angiotensin II-induced cardiac fibrosis by sponging miR-29b-3p [45]. In addition, Zhu et al. found circNFIB is downregulated in cardiac fibrosis in vivo and in vitro, and upregulation of circNFIB attenuates cardiac fibrosis by sponging miR-433 [46].
2.4. Cardiac hypertroph Heart failure is one of the leading causes to death worldwide, and there is a close link between cardiac hypertrophy and heart failure. Cardiac hypertrophy is highly possible to eventually develops into heart failure. It is believed that there are many factors affecting cardiac function and participating in myocardial hypertrophy, such as G protein coupled receptors, epinephrine and angiotensin [36,37].
2.6. Diabetic cardiomyopath Diabetic patients have a significantly increased risk of developing diabetic cardiomyopathy [47,48]. CircRNA_000203 was shown 3
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upregulated in the diabetic mouse myocardium and in Ang-II-induced mouse cardiac fibroblasts. CircRNA_000203 contains two sites that bind to mirRNA-26p-5p, and mirRNA-26p-5p can play an anti-fibrosis role by binding to Colla2 and CTGF. Overexpression of circRNA_000203 can decrease the anti-fibrosis effect of mir-26p-5p in myocardial fibrosis. In addition, blocking miR-26p-5p could produce protective effect on myocardial fibrosis consistent with overexpression of circRNA_000203. Therefore, the circRNA_000203 can play an anti-fibrosis through the circRNA_000203-mirRNA-26p-5p–Colla2 or CTGF axis [49]. Furthermore, Yang et al. found circ_0076631 was increased both in high-glucose-treated cardiomyocytes and in the serum of diabetic patients, and can sponged an endogenous miR-214-3p/caspase-1 to sequester and inhibit its expression [50].
oxygen consumption, as well as to myocardial apoptosis, necrosis and fibrosis in ischemic site. Studies have found that circRNA was associated with myocardial cell regeneration and vascular regeneration in ischemic heart disease [54]. The circRNA termed sodium/calcium exchanger 1 (ncx1) promotes the cardiomyocyte apoptosis through the circ-ncx1-miR-133a-3p–CDIP1(cell death-inducing protein) axis. Overexpression of circ-ncx1 can promotes the cardiomyocyte apoptosis, and the binding of circ-ncx1 to miR-133a-3p decreases the activity of miR133a-3p, thus upregulating the target gene CDIP1, and eventually aggravating the development of ischemic heart disease [55]. Furthermore, Zhou et al. found circRNA ACR attenuates myocardial ischemia/reperfusion injury by suppressing autophagy via modulation of the Pink1/ FAM65B pathway [56].
2.7. Aortic aneurys
3. Conclusion and future perspectiv
Aortic aneurysm, which refers to the pathological dilatation of aorta, and it also has a high risk of death and the mechanism is complex [51,52]. Research reported that hsa-circ-000595 is associated with apoptosis of aortic smooth muscle, which in turn affects the occurrence of aortic aneurysms. The expression of hsa-circ-000595 in aortic smooth muscle cells was up-regulated under hypoxic conditions. The apoptosis of aortic smooth muscle cells was decreased by knockdown of hsa-circ000595. It was also found that hsa-circ-000595 acted as the cavernous body of mir-19a, and the decrease of hsacirc-000595 could increase the expression of mir-19a and reduce the apoptosis of smooth muscle cells [53]. Though the mechanism of miR-19a affecting smooth muscle cells needs to be further explored, the discovery of hsa-circ-000595 could provide a new genetic basis to the diagnosis and treatment of aortic aneurysms.
To the best of our knowledge, this is the most comprehensive review to explore the current knowledge concerning circRNA–miRNA–mRNA axis in the pathogenesis and development of CVDs and abnormal conditions(Fig. 1). CircRNA, as a newly discovered molecule with special biological function, has good specificity and stability. Its potential as a biomarker has been proved in cardiovascular diseases. Cardiovascular disease is a kind of disease with high morbidity and mortality. The mechanism of its occurrence and development is not clear. Revealing the occurrence and development of cardiovascular disease at the molecular level will provide a more efficient and accurate method for its early diagnosis, treatment and prognosis of the disease. The study on the role of cyclic RNA in cardiovascular diseases has revealed a new angle, which provides a new idea for the diagnosis and prognosis of cardiovascular diseases. Although circRNAs have increasingly been found to be differentially expressed between diseased cardiovascular tissues and normal tissues, the role of circRNA in cellular and molecular mechanisms were partly known. At present, only a few circRNAs, such as HRCR and circRNA Cdr1as have been proved to be related to cardiovascular diseases, most
2.8. Ischemic heart diseas Ischemic heart disease is a kind of coronary artery stenosis, which leads to the imbalance between coronary blood flow and myocardial
Fig. 1. CircRNAs function as ceRNAs in cardiovascular diseases. Red lines represent promotion, black lines represent suppression. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) 4
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of which play a role as the cavernous body of miRNA, suggesting that there may be some relationship between the two. CircRNA-miRNA targeting mRNA can not only be used as a promising biomarker for early diagnosis and stratification, but also as an advanced molecular technology to simulate or manufacture therapeutic agents. [17]
Authors' contributions
[18]
Qiang Su designed the research and wrote the paper; Qiang Su and Xiangwei Lv interpreted the data. All authors read and approved the final manuscript.
[19] [20]
Fundin This work was received National Natural Science Foundation of China (Grant No. 81600283) and Guangxi Natural Science Foundation (Grant No. 2017GXNSFAA198069).
[21] [22]
Declaration of Competing Interest
[23]
The authors declare that they have no competing interests.
[24]
Acknowledgement [25]
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