Scholarly article on topic 'Regulatory non-coding RNAs in acute myocardial infarction'

Regulatory non-coding RNAs in acute myocardial infarction Academic research paper on "Basic medicine"

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J. Cell. Mol. Med.
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Academic research paper on topic "Regulatory non-coding RNAs in acute myocardial infarction"

Regulatory non-coding RNAs in acute myocardial infarction

Yuan Guo, Fei Luo, Qiong Liu, Danyan Xu *

Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China

Received: July 16, 2016; Accepted: October 9, 2016

• Introduction • NcRNAs modulate angiogenesis in ischaemic areas

• NcRNAs mediate cardiomyocyte apoptosis • NcRNAs regulate fibrosis in infarct regions

- Non-beneficial miRNAs in cardiomyocyte apoptosis • LncRNA/circRNA-miRNA-mediated interaction

- Protective miRNAs in cardiomyocyte apoptosis • Conclusion and clinical perspectives

- LncRNAs and circRNAs in cardiomyocyte apoptosis • Acknowledgements

• NcRNAs regulate inflammation around infarct areas • Conflict of interest


Acute myocardial infarction (AMI) is one of the most common cardiovascular diseases that leads to high mortality and morbidity globally. Various therapeutic targets for AMI have been investigated in recent years, including the non-coding RNAs (ncRNAs). NcRNAs, a class of RNA molecules that typically do not code proteins, are divided into several subgroups. Among them, microRNAs (miRNAs) are widely studied for their modulation of several pathological aspects of AMI, including cardiomyocyte apoptosis, inflammation, angiogenesis and fibrosis. It has emerged that long ncRNAs (lncRNAs) and circular RNAs (circRNAs) also regulate these processes via interesting mechanisms. However, the regulatory functions of ncRNAs in AMI and their underlying functional mechanisms have not been systematically described. In this review, we summarize the recent findings involving ncRNA actions in AMI and briefly describe the novel mechanisms of these ncRNAs, highlighting their potential application as therapeutic targets in AMI.

Keywords: acute myocardial infarction • microRNAs • long non-coding RNAs • circular RNAs • apoptosis • inflammation • angiogenesis • fibrosis


AMI is the most severe cardiovascular event, resulting in high morbidity and mortality worldwide. Atherosclerosis-induced coronary artery luminal occlusion and plaque rupture is the most common cause of AMI, which is characterized by endothelial injury, lipid accumulation and the formation of atherosclerotic plaque. Cardiomyocyte necrosis and apoptosis with subsequent excessive inflammation are the main causes of myocyte injury and loss in the pathological process of AMI [1]. Yet, angiogenesis in the ischaemic area promotes cardiomyocyte survival [2]. Eventually, the extent of infarcted ventricular remodelling by fibrosis determines cardiac function and prognosis. Therefore, approaches that inhibit cell death and ventricular fibrosis, regulate inappropriate inflammatory response and promote angiogenesis after AMI are promising therapeutic approaches for improving the prognosis of patients with AMI.

Correspondence to: Danyan XU, E-mail:

Regulatory ncRNAs are a class of RNA molecules that typically do not code proteins but that functionally regulate protein expression [3]. It has been suggested that as much as 98% of the human genome encodes non-coding transcripts [4]. NcRNAs are classified into subgroups according to their transcript length and include small, medium length and lncRNAs. It has been speculated that these non-coding transcripts are emerging key regulators of gene expression under physiological and pathological conditions. Moreover, there are emerging data that ncRNAs are of crucial importance in cardiovascular diseases, particularly AMI. The AMI-related ncRNAs that are often studied are miRNAs; lncRNAs and circRNAs, emerging regulatory factors of the pathophysiological processes of AMI. More interestingly, cross-regulatory networks between miRNAs and lncRNAs/circRNAs were recently identified, endowing these non-coding transcripts with more potential and comprehensive functions [5].

MiRNAs, the most widely studied small ncRNAs, are about 18-22 nucleotides long and regulate gene expression at post-transcriptional level through transcript degradation or translational repression [6].

doi: 10.1111/jcmm.13032

© 2016 The Authors.

Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Previous studies have revealed critical roles of miRNAs as regulators of the growth, development, function and stress responsiveness of the heart, providing potential therapeutic targets for heart disease [7]. MiRNAs are also considered critical regulators for a diverse range of biological processes, including apoptosis, fibrosis, inflammation, angiogenesis and repair in infarcted hearts [8]. Therefore, regulating the levels of certain miRNAs after AMI may be helpful for limiting tissue injury, promoting neovascularization and controlling ventricular remodelling, subsequently improving long-term prognosis.

LncRNAs are a diverse class of heterogeneous transcribed RNA molecules ranging from 200 to 100,000 nucleotides in length. As a newly identified ncRNA in function, the common feature of lncRNAs is that they do not act as vehicles for protein translation [9]. Similarly, lncRNAs function as regulators of protein expression. As lncRNAs are also essential for correct and timely regulation of protein expression, they are not only considered to perform functions during the development of an organism, but also play roles in various physiological and pathological conditions, including AMI, even though very little is known of them at present. Furthermore, as lncRNAs are more likely to be expressed in a tissue-/cell type-specific manner and can bind to miRNAs to communicate with other RNA targets, lncRNAs have garnered much research attention [10].

CircRNAs, newly discovered endogenous ncRNAs in function, are involved in an area of much research activity because they lack an open end, preventing conventional RNA degradation pathways and acting as more stable RNA molecules [11,12]. CircRNAs are also expressed in a manner of specific to tissue and developmental stage. Similarly, as potential gene regulators, circRNAs modulate many disorders. To date, the function of circRNAs in disease processes has seldom been studied; only a few circRNAs have been proven to play or potentially play cardioprotective roles by acting as molecular sponges targeting miRNAs. Additional exploration of circRNA function will further describe an emerging new factor in the pathological processes of AMI.

Previous studies have reported the importance of both miRNAs and lncRNAs in regulating the pathological processes of AMI; the newly identified functional non-coding transcripts, circRNAs, have emerged as modulators of AMI. However, the most recently identified ncRNAs and their communication in AMI have not been comprehensively reviewed. Accordingly, we have summarized these ncRNAs and their implicated interactions in modulating cardiomyocyte apoptosis, inflammation, angiogenesis and fibrosis after the acute setting to gain insight into their therapeutic potential in AMI.

NcRNAs mediate cardiomyocyte apoptosis

Cardiomyocyte necrosis is a key cellular event in infarct cardiomyopathy, which is generally viewed as an uncontrolled process in AMI. Apoptosis is a highly regulated process that is activated via death receptors in the plasma membrane and that mainly occurs in ischaemic areas. The mitochondria-dependent apoptotic pathway is closely controlled by the ratio of B-cell lymphoma 2 (Bcl-2) and the pro-apoptotic effector Bcl-2-associated X protein (BAX). When the

pro-apoptotic effector disrupts the mitochondrial membrane, apoptosis effector caspases are activated and execute apoptosis. Furthermore, extrinsic receptor-mediated apoptosis is engaged when certain death receptor ligands, such as FAS ligand and tumour necrosis factor-« (TNF-a), bind their death receptors on the plasma membrane. Then, caspase-8 is activated in a manner Fas-associated protein with death domain (FADD)-dependent manner. The effector caspases converge on these two pathways. The pro-apoptotic pathway is counteracted by a series of anti-apoptotic mediators, including the phosphoinositide-3-kinase (PI3K)/AKT pathway. Numerous miRNAs regulate cardiomyocyte apoptosis (Fig. 1A).

Non-beneficial miRNAs in cardiomyocyte apoptosis

Some non-beneficial miRNAs decrease the Bcl-2/BAX ratio to promote apoptosis. MiR-15a and miR-15b are up-regulated in response to cardiac ischaemia/reperfusion injury and are involved in myocardial apoptosis by targeting Bcl-2 and the caspase signalling pathway [13]. By contrast, miR-15 inhibition is protective against cardiac injury after MI [14]. Forced expression of miR-497 induced apoptosis in neonatal rat cardiomyocytes, but silencing miR-497 using a miR-497 sponge significantly reduced apoptosis; this process was also involved in reducing the expression of the anti-apoptosis gene BCL-2 [15].

Similarly, miR-24 increases cardiovascular apoptosis in the infarcted myocardium [16]. In mice, local adenovirus-mediated overexpression of miR-24 increased the percentage of apoptotic cardiomyocyte nuclei by 2.2-fold. In addition, miR-24 exerts its pro-apoptotic function by targeting the pro-apoptotic gene BCL2-like 11 apoptosis facilitator (BIM) that in turn represses Bcl-2 expression [17]. MiR-208a also has pro-apoptotic effects on ischaemic cardiomyocytes, which are related to the increased expression of the pro-apoptosis gene BAX in ischaemic cardiomyocytes [18]. MiR-34a has also been confirmed as an important pro-apoptosis regulator in AMI [19]; it is increased after ischaemia and exerts its pro-apoptosis function by negatively regulating the anti-apoptotic protein aldehyde dehydrogenase-2 (ALDH2), which also decreases the Bcl-2/BAX ratio [20].

Several other miRNAs promote cardiomyocyte apoptosis after AMI by directly targeting the caspase family. Wang et al. [21] demonstrated that miR-874 is involved in H2O2-induced cardiomyocyte death by increasing caspase-8 after MI. The authors further confirmed the apoptosis-promoting function of miR-874 using a miR-874 antagomir that significantly attenuated H2O2-induced cell death. MiR-155 deficiency prevented ischaemia/reperfusion injury-induced apoptosis in an AMI mouse model [15]. Furthermore, Eisenhardt et al. [22] found that miR-155 aggravated apoptosis post-AMI by increasing the expression of the apoptosis-related caspase-3.

MiR-92a promoted apoptosis in the heart after MI, and treatment with antagomiR-92a to inhibit miR-92a in vivo reversed this process. Unfortunately, the antagomiR-92a-induced reduction in cardiomyocyte apoptosis was not observed in vitro, suggesting that an indirect mechanism mediates the anti-apoptotic activity of antagomiR-92a in vivo [8]. Overall, inhibiting these miRNAs may be new therapeutic approaches in AMI.

Fig. 1 NcRNAs regulate cardiomyocyte apoptosis after acute myocardial infarction. (A) MiRNAs mediate cardiomyocyte apoptosis. Pro-apoptotic miRNAs are marked in blue including miR-15, miR-497, miR-208a, miR-34a, miR-24, miR-874 and miR-155. Anti-apoptotic miRNAs are marked in red including miR-210, miR-214, miR-1, miR-21, miR-149, miR-133a, miR-499 and miR-130a. (B) LncRNAs/circRNAs interact with miRNAs to modulate cardiomyocyte apoptosis. Pro-apoptotic lncRNAs/circRNAs are marked in blue including APF, NRF and CDR1as. Anti-apoptotic lncRNAs are marked in red including CARL and H19. APF, autophagy-promoting factor; ATG7, autophagy-related protein 7; ALDH2, aldehyde dehydrogenase 2; Apaf-1, apoptotic protease-activating factor-1; Bcl-2, B-cell lymphoma 2; BAX, Bcl-2-associated X protein; BIM, BCL2-like 11 apoptosis facilitator; CARL, cardiac apoptosis-related lncRNA; CDR1as, cerebellar degeneration-related protein 1 transcript; FADD, Fas-associated protein with death domain; NRF, necrosis-related factor; PI3K, phosphoinositide-3-kinase; PTP1B, protein tyrosine phosphatase-1B; PTEN, phosphatase and tensin homolog; PARP, pro-apoptotic gene poly ADP-ribose polymerase; PHB2, prohibitin-2; RIPK1, receptor-interacting serine/threonine protein kinase 1; RIPK3, receptor-interacting serine/threonine protein kinase 3; TNF-a, tumour necrosis factor-a.

Protective miRNAs in cardiomyocyte apoptosis

The PI3K/AKT pathway is the main signalling pathway for inhibiting apoptosis that is consistently activated with activation of the pro-apoptotic pathway after AMI. Several miRNAs protect cardiomyocytes against apoptosis after AMI by activating PI3K and its downstream regulators. MiR-210 inhibited apoptosis in mice after MI, and miR-210 overexpression prevented cardiomyocyte apoptosis by down-regulating protein tyrosine phosphatase-1B that subsequently activated the PI3K/AKT pathway [23]. MiR-214 is a newly identified miRNA that inhibits cardiomyocyte apoptosis. Overexpression of miR-214 in an AMI rat model decreased the size of the infarcted area, improved heart function and haemodynamic status and inhibited left ventricular remodelling. The miR-214-mediated protective mechanism is based on the repression of phosphatase and tensin homolog (PTEN), which acts as a PI3K inhibitor [24]. In an AMI mouse model, overexpressing miR-1 in embryonic stem cells and transplanting them into infarcted myocardium inhibited cardiomyocyte apoptosis and improved cardiac function after 4-week treatment, which was related to reduced PTEN levels and caspase-3 activity [25, 26]. Similarly, miR-21 was involved in trimetazidine-induced anti-apoptosis during ischaemia/reperfusion injury, and increased miR-21 expression inhibited cardiomyocyte apoptosis [27]. Forced expression of miR-21 up-regulated PI3K/AKT activity by suppressing PTEN expression and increasing the Bcl-2/

BAX ratio, which in turn reduced caspase-3 expression and finally counteracted the apoptotic effect [28].

Another mechanism of the miR-21-induced anti-apoptosis effect in H2O2-mediated cardiomyocytes is directly inhibiting pro-apoptotic protein programmed cell death 4 (PDCD4) expression [29-31]. Cardiac-specific miR-499 was widely reported as an important biomarker reflecting myocardial damage in AMI [32, 33]. Overexpression of miR-499 favoured cardiomyocyte survival and inhibited apoptosis. More interestingly, it was recently reported that miR-499 protects cardiomyocytes from H2O2-induced apoptosis and rat AMI models by suppressing expression of the pro-apoptotic protein PDCD4 and phosphofurin acidic cluster sorting protein 2, thereby blocking Bid expression and BID mitochondrial translocation [34, 35].

Other miRNAs also directly target the caspase family. Dakhlallah et al. [36] transfected mesenchymal stem cells with miR-133a and found that it prevented apoptosis by directly targeting apoptotic pro-tease-activating factor-1, which down-regulated caspase-9 and cas-pase-3 expression. Lu et al. [37] found that MI induced myocardial apoptosis and increased caspase-3/7 and caspase-8 activity by 105.6% and 71.3%, respectively, when compared with sham controls, while lentivirus transfection of miR-130a overexpression markedly reduced caspase-3/7 and caspase-8 activity by 22.9% and 30.8%, respectively, as compared with the controls. Ding et al. [38]

reported that miR-149 contributed to inhibition of apoptosis after MI by regulating the pro-apoptotic protein PUMA, which in turn activated caspase-9 to promote apoptosis. Hence, activating these miRNAs is a promising target for treating AMI.

LncRNAs and circRNAs in cardiomyocyte apoptosis

Recently, some lncRNAs and circRNAs were identified as vital biomarkers and promising therapeutic targets in AMI [39,40] (Table 1 and Fig. 1B). The circulating lncRNA urothelial carcinoma-associated 1 (UCA1) was down-regulated within 3 days after the onset of AMI [41]. Microarray analysis of MI mice showed that two lncRNAs, MI-associated transcript 1 and 2, were significantly up-regulated fivefold and 13-fold, respectively, after MI [42]. Moreover, myosin heavy chain-associated RNA transcripts (MHRT), a heart-specific lncRNA, were significantly elevated in the blood of patients with AMI as compared with healthy controls (P < 0.05). In a H2O2-induced neonatal rat cardiac myocyte injury model, MHRT was also up-regulated in injured cardiac myocytes, and short interfering RNA knock-down of the Mhrt gene led to more apoptotic cells than in the non-target control (P < 0.01), indicating that MHRT is not only a biomarker of ischaemic cardiomyocytes but also a protective lncRNA for cardiomyocytes and a promising therapeutic target of AMI [43].

In addition, other lncRNAs interact with miRNAs to exert their apoptotic inhibitory function. MiR-188-3p inhibited autophagy under pathological conditions by targeting autophagy-related protein 7.

Wang et al. [44] found that the lncRNA autophagy-promoting factor regulated autophagic cell death by down-regulating miR-188-3p, thereby promoting autophagy after MI. Cardiac apoptosis-related lncRNA (CARL) suppressed mitochondrial fission and apoptosis by decreasing endogenous miR-539 levels by acting as a sponge, which in turn up-regulated prohibitin 2 expression to inhibit apoptosis [45]. MiRNA-103/107 and the lncRNA H19 also mediate cardiomyocyte survival after AMI. H19 bound directly to miR-103/107, suppressing receptor-interacting serine/threonine protein kinase (RIPK)1/RIPK3 and FADD-dependent death in foetal cardiomyocyte-derived H9C2 cells and in an MI mice model [46]. The lncRNA necrosis-related factor (NRF) targets miR-873 and RIPK1/RIPK3 to regulate cardiomyocyte death. An endogenous sponge RNA, NRF repressed miR-873 expression, which in turn increased RIPK1/RIPK3 and cardiomyocyte death [47]. Thus, these lncRNAs are potential therapeutic targets of AMI by inhibiting cardiomyocyte death.

The circRNA cerebellar degeneration-related protein 1 transcript (CDR1as) has 63 conserved binding sites for miR-7, by which CDR1as could function as an miR-7 sponge to regulate post-tran-scriptional gene expression [48]. Intriguingly, Geng et al. [49] recently reported the CDR1as/miR-7a pathway in cardiomyocytes and explored the underlying function of miR-7a in protection against AMI. They found that CDR1as and miR-7a were both up-regulated in MI mice or cardiomyocytes under hypoxia treatment. However, overexpression of CDR1as in vivo increased cardiac infarct size, while miR-7a overexpression reversed these changes. Furthermore, CDR1as functioned as a powerful miR-7a sponge in myocardial cells, and miR-7a protected cardiomyocytes from injury after MI by inhibiting

Table 1 Long non-coding RNAs as biomarkers in acute myocardial infarction

■ LncRNAs ■ Regulation after AMI Relation to other biomarkers

Yan et al. [41] UCA1 Down-regulation Inversely related to miR-1 level

Zangrando et al. [42] MIRT1/MIRT2 Up-regulation Negatively correlated with infarct size; positively correlated with EF value

Zhang et al. [43] MHRT Up-regulation Inversely related to cardiomyocyte apoptosis

Vausort et al. [56] ANRIL Down-regulation Positively correlated to lymphocytes and monocytes; negatively related to MMP9, WBC, neutrophils, platelets

Vausort et al. [56] MIAT Down-regulation Positively related to lymphocytes; negatively related to neutrophils, platelets

Vausort et al. [56] MALAT1 Up-regulation Negatively related to platelets

Vausort et al. [56] aHIF Up-regulation Positively related to WBC, neutrophils CRP, MMP9, TIMP1; negatively related to lymphocytes

Qu et al. [80] NONMMUT022554 Up-regulation Positively correlated with fibrosis gene expression

ANRIL, cyclin-dependent kinase inhibitor 2B antisense RNA 1; aHIF, hypoxia-inducible factor 1A antisense RNA 2; CRP, C-reactive protein; EF, ejection fraction; MIRT1, MI-associated transcript 1; MIRT2, MI-associated transcript 2; MIAT, myocardial infarction-associated transcript; MALAT1. metastasis-associated lung adenocarcinoma transcript 1; MMP9, matrix metalloproteinase 9; TIMP1, tissue inhibitor of metallopro-teinase 1; UCA1, urothelial carcinoma-associated 1; WBC, white blood cell.

the expression of the pro-apoptotic gene poly ADP-ribose polymerase (PARP) and SP1. This indicates that CDR1as may be a promising anti-apoptosis target.

NcRNAs regulate inflammation around infarct areas

Cardiac cell death after ischaemia subsequently induces inflammatory cascades. Proper inflammatory reaction helps to clear cellular debris and trigger repair mechanisms after AMI, while excessive inflammation is a critical factor in aggravating cardiomyocyte injury and death. Therefore, modulating excessive inflammatory response is essential for preventing cardiomyocyte death [50]. Some miRNAs play critical roles in reducing the inflammatory response after AMI (Table 2).

The inflammatory response is mainly involved in monocyte cell migration and the production of a cluster of proinflammatory cytokines, which then initiate a cascade reaction. The overexpression of miR-150 in mice was critical for monocyte migration and proinflammatory cytokine production, resulting in cardioprotective effects against AMI injury. This was related to miR-150 inhibition of chemo-kine receptor 4 and subsequently reduced inflammatory Ly-6Chigh monocyte invasion after AMI [51]. Furthermore, the inflammation-related miR-155 was down-regulated by approximately 60% in patients with acute coronary syndrome, which was consistent with the expression of interleukin-17A in peripheral blood mononuclear cells, suggesting that it is essential for T helper cell differentiation [52]. A similar study reported that, in an AMI mouse model, miR-155 significantly increased TNF-a, IL-1b and CD105 expression and leucocyte infiltration after AMI, and that miR-155 deficiency prevented ischaemia/reperfusion injury-induced tissue necrosis and attenuated inflammatory cell infiltration [22].

There is evidence that the inflammation-related miR-146a and miR-21 are increased by approximately twofold in patients with acute coronary syndrome [52]. Liu et al. [53] found that miR-146a and miR-21 were positively related with MI, which was consistent with the C-reactive protein levels and leucocyte counts, indicating that the two miRNAs are involved in post-AMI inflammation. Ibrahim et al. [54] reported post-AMI inflammation in miR-146a-enriched exo-somes and that miR-146a performed its function by suppressing IL-1

receptor-associated kinase 1 and TNF receptor-associated factor 6 expression. Toldo et al. [55] found that exogenous hydrogen sulphide reduced myocardial ischaemia and inflammation in cardiomyocytes after MI by attenuating the formation of inflammasomes in a miR-21-dependent manner. These inflammatory miRNAs might be potent therapeutic targets in the setting of ischaemic heart disease.

Recent findings have also determined that several lncRNAs act as inflammatory biomarkers after AMI (Table 1). There was a positive association between cyclin-dependent kinase inhibitor 2B antisense RNA1 and the percentage of lymphocytes and monocytes, but it was inversely associated with white blood cell count, neutrophil count, platelet count and matrix metalloproteinase 9 (MMP9). MI-associated transcript (MIAT) was positively associated with lymphocyte count and negatively associated with neutrophil and platelet counts. Metastasis-associated lung adenocarcinoma transcript 1 was negatively associated with platelet count. Hypoxia-inducible factor 1A antisense RNA 2 was also positively associated with white blood cell count, neutrophil count, C-reactive protein, MMP9 and tissue inhibitor of metalloproteinase-1 [56]. These findings suggest that these lncRNAs play important roles in AMI.

NcRNAs modulate angiogenesis in ischaemic areas

Angiogenesis is a critical component in post-AMI early tissue repair that also participates in limiting the infarct size and reducing myocardial apoptosis. MiRNAs also modulate angiogenesis (Fig. 2 and Table 3). MiR-92a is the most widely studied miRNA for inhibiting angiogenesis after AMI. Bellera et al. [57] demonstrated that a single intracoronary administration of antagomiR-92a encapsulated in specific microspheres inhibited miR-92a, resulting in significant vessel growth in a local, selective and sustained manner in a pig model of AMI. Bonauer et al. [8] reported that miR-92a controlled blood vessel growth in an MI mouse model by decreasing integrin «5; systemic administration of antagomir to inhibit miR-92a enhanced blood vessel growth and functional recovery of damaged tissue. Similarly, Hinkel et al. [58] found that local delivery of locked nucleic acid (LNA)-modi-fied antisense miR-92a directed against miR-92a expression significantly reduced infarct size and improved the recovery of cardiac

Table 2 MicroRNAs regulated inflammation in acute myocardial infarction

NcRNAs Function Targets Modulation

Liu etal. [51] miR-150 Inhibit inflammation Inhibit CXCR4 Increase expression

Yao et al. [52] miR-155 Promote inflammation Modulation T helper cells differentiation Inhibit expression

Eisenhardt et al. [22] miR-155 Promote inflammation Increase TNF-a, IL-1b, CD105 and leucocyte infiltration Inhibit expression

Ibrahim et al. [54] miR-146a Inhibit inflammation Suppress IRAK1 and TRAF6 Increase expression

Toldo et al. [55] miR-21 Inhibit inflammation Attenuate the formation of inflammasome Increase expression

CXCR4, chemokine receptor 4; IL-1b, interleukin-1b; IRAK1, interleukin-1 receptor-associated kinase 1; TNF-« tumour necrosis factor-«; TRAF6, tumour necrosis factor receptor-associated factor 6.

function in pigs after MI by targeting integrin a5. Consequently, miR-92a may serve as a valuable therapeutic target in the ischaemic disease setting.

Several other miRNAs, including miR-26a, miR-24, miR-34c and miR-375, are involved in suppressing angiogenesis in AMI. MiR-26a overexpression in an AMI mouse model and in human subjects with acute coronary syndrome attenuated angiogenesis. By contrast, miR-26a inhibitor induced angiogenesis by inhibiting bone morphogenic protein (BMP)/SMAD1 signalling, thereby reducing myocardial infarct size [59]. Moreover, direct antagomirs against miR-24 or local aden-ovirus-mediated miR-24 decoy delivery improved recovery after AMI in mice. MiR-24 inhibition increased blood vessels in infarcted myocardium by increasing endothelial nitric oxide synthase (eNOS) and decreasing the pro-angiogenic p21 protein-Cdc42/Rac-activated kinase 4 (PAK4) and globin transcription factor binding protein 2 (GATA2) [16, 17]. High glucose-induced miR-34c expression impaired angiogenic activity after MI by reducing stem cell factor (SCF) and increasing Kruppel-like factor 4 (KLF4) and plasminogen activator inhibitor-1 (PAI-1) [60]. MiR-375 also inhibits angiogenesis after MI; IL-10-induced miR-375 decrease exerted a pro-angiogenic effect by up-regulating 3-phosphoinositide-dependent protein kinase-1 (PDK-1) [61]. Accordingly, inhibiting these harmful miRNAs after AMI may be a promising therapeutic target and may improve the prognosis after acute settings.

Table 3 Non-coding RNAs regulated angiogenesis in acute myocardial infarction

NcRNAs Function Targets Modulation

Bonauer et al. [8] miR-92a Inhibit angiogenesis Decrease ITGA5 Inhibit expression

Hinkel et al. [58] miR-92a Inhibit angiogenesis Decrease ITGA5 Inhibit expression

Icli et al. [59] miR-26a Inhibit angiogenesis Inhibit BMP/SMAD1 Inhibit expression

Meloni etal. [17] miR-24 Inhibit angiogenesis Decrease eNOS, increase PAK4, GATA2 Inhibit expression

Kang et al. [60] miR-34c Inhibit angiogenesis Decrease SCF increase KLF4, PAI-1 Inhibit expression

Garikipati etal. [61] miR-375 Inhibit angiogenesis Negatively regulate PDK-1 Inhibit expression

Huang et al. [63] miR-126 Promote angiogenesis Up-regulation of VEGF, bFGF and DLL-4 Increase expression

Wang et al. [64] miR-126 Promote angiogenesis Promoting VEGF, FGF repressing SPRED1 Increase expression

van Mil et al. [65] miR-1 Promote angiogenesis Inhibit SPRED1 Increase expression

Chen et al. [67] Let-7 Promote angiogenesis Suppress AGO1, increase VEGF produce Increase expression

Hu et al. [23] miR-210 Promote angiogenesis Release angiogenic factors; decrease EFNA3 expression Increase expression

Ghosh et al. [68] miR-424 Promote angiogenesis stabilize HIF-a Increase expression

Yan et al. [69] \ MIAT Promote angiogenesis Decrease miR-150-5p Increase VEGF Increase expression

AGO1, argonaut 1; BMP, bone morphogenic proteins; bFGF, basic fibroblast growth factor; DLL-4, notch ligand Delta-like 4; eNOS, endothelial nitric oxide synthase; GATA2, globin transcription factor binding protein 2; HIF-a, hypoxia-inducible factor-a; ITGA5, integrin a5; KLF4, Kruppel-like factor 4; MIAT, myocardial infarction-associated transcript; PAK4, pro-angiogenic p21 protein-Cdc42/Rac-activated kinase 4; PAI-1, plasminogen activator inhibitor-1; PDK-1, 3-phosphoinositide-dependent protein kinase-1; SPRED1, sprouty-related EVH1 domain-containing protein 1; SCF, stem cell factor; VEGF, vascular endothelial growth factor.


( ) r~.-\

v-/ f miR-424 J

( miR-210 )

v-J Pro-angiogenesis

Fig. 2 NcRNAs mediate angiogenesis around infarct areas after acute myocardial infarction. Anti-angiogenesis ncRNAs are marked in black including miR-92a, miR-26a, miR-24, miR-34c, miR-375 and miR-150-5p. Pro-angiogenesis ncRNAs are marked in red including miR-126, miR-1, miR-210, miR-424, Let-7 and MIAT. MIAT, myocardial infarction-associated transcript.

However, a cluster of miRNAs increases angiogenesis after AMI. MiR-126 is considered a positive regulator of angiogenesis after AMI [62]. Huang et al. [63] reported that miR-126 overexpression up-regulated vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF) and notch ligand Delta-like 4 (DLL4) in mesenchymal stem cells and thereby enhanced functional angiogenesis in the ischaemic myocardium. Wang et al. [64] determined that the pro-angiogenic actions of miR-126 after MI were related to repressed expression of sprouty-related EVH1 domain-containing protein 1 (SPRED1), an intracellular inhibitor of angiogenic signalling. Furthermore, miR-1 also enhanced the angiogenic effects of progenitor cells by inhibiting SPRED1 expression [65].

Other miRNAs have been identified to promote angiogenesis after AMI. Let-7 plays an active role in the pathogenesis of MI [66]. Chen et al. [67] reported that hypoxia induced let-7 expression, which suppressed Argonaut 1 (AGO1) and increased VEGF to promote angiogenesis. Using an MI mouse model, Hu et al. [23] demonstrated that miR-210 improved angiogenesis by releasing angiogenic factors; overexpressing miR-210 resulted in the down-regulation of the anti-angiogenic gene EFNA3 and promoted angiogenesis. Ghosh et al. [68] reported that miR-322/424 was up-regulated after MI and hypoxia, and increased miR-424 targeted cullin-2 to stabilize hypoxia-indu-cible factor a isoforms and promote angiogenesis. Accordingly, enhancing the expression of the pro-angiogenic miRNAs might be a valuable therapeutic target in AMI.

Research has seldom discussed the roles of lncRNAs in angiogenesis after AMI. Previous findings have only reported that MIAT is related to angiogenesis, functioning as a competing endogenous RNA by sponging miR-150-5p in retinal endothelial cells to regulate VEGF levels. That is, MIAT overexpression acted as a sink for miR-150-5p, which in turn increased VEGF levels and promoted angiogenesis [69]. Further exploration of more lncRNAs involved in angiogenesis may determine whether they are potent factors that promote angiogenesis after AMI.

NcRNAs regulate fibrosis in infarct regions

Cardiac fibroblasts are activated and subsequently produce excessive extracellular matrix (ECM) proteins after MI, which ultimately impairs cardiac function and leads to interstitial fibrosis and remodelling of the heart. Accordingly, inhibiting excessive ECM secretion and deposition is an important therapeutic strategy for improving the prognosis of AMI. Several miRNAs have been implicated in the pathology of cardiac fibrosis after AMI (Fig. 3). Inhibiting the miR-34 family improved cardiac function in mice and attenuated pathological remodelling after MI. Bernardo et al. [70] reported that silencing entire miR-34 family protected the heart against pathological cardiac remodelling and improved cardiac function. The authors also found elevated collagen (Col) 1«1 gene expression in the infarct zone after MI in mice. However, MI mice treated with LNA-anti-miR-34 trended towards lower Col1«1 expression. Huang et al. [71] further demonstrated that inhibiting miR-34a reduced the severity of experimental cardiac

Fig. 3 MiRNAs modulate cardiac fibrosis in infarct regions after acute myocardial infarction. Pro-fibrosis miRNAs are marked in blue including miR-34, miR-208a and miR-21. Anti-fibrosis miRNAs are marked in red including miR-29, miR-101a, miR-24 and miR-711. Col1: collagen 1, Col1a1: collagen 1a1, p-MHC: p-myosin heavy chain, FBN1: fibrillin 1, TGFp: transforming growth factor beta, TGFpRIII: transforming growth factor beta receptor III.

fibrosis in mice after AMI, indicating that miR-34a plays a critical role in the progression of cardiac tissue fibrosis by directly inducing pro-fibrotic pathway transforming growth factor beta 1 (TGFp1)/Smad4.

Furthermore, miR-208aand miR-21 were also involved in promoting cardiac fibrosis after MI. MiR-208a was increased in rats with AMI, which significantly increased the area of myocardial fibrosis compared with the sham group. It was further believed that the cardiac fibrosis action induced by miR-208a was related to endoglin activation and p-myosin heavy chain expression [72]. MiR-21 is an important regulatory molecule in the pathogenic process of myocardial fibrosis after MI. MiR-21 was up-regulated in the border zone of the infarcted region after AMI in mice, which could increase the collagen content and lead to cardiac fibrosis, which was partially related to inhibition of transforming growth factor beta receptor III (TGFpRIII) expression [73]. Therefore, inhibiting these miRNAs may be a promising strategy for treating cardiac fibrosis after AMI.

However, some miRNAs inhibit cardiac fibrosis after AMI, and miR-29 is the most well-studied anti-fibrosis miRNA. van Rooij et al. [74] showed that miR-29 expression was down-regulated after MI, thereby inducing collagen overexpression and cardiac fibrosis. They also reported that the mechanism of collagen overexpression induced by low miR-29 levels was related to up-regulation of its targets Col1«1, Col1«2, Col1«3 and fibrillin 1 in the infarcted region. Melo et al. [75] also reported that swimming training improved ventricular function after MI in rats by improving cardiac miR-29a and miR-29c levels, thereby preventing COLIAI and COLIIIAI expression in the border region and remote myocardium of the infarcted left ventricle.

Additionally, several other miRNAs, including miR-101a, miR-24 and miR-711, also counteract cardiac fibrosis and attenuate the remodelling process after MI. MiR-101a is a novel identified anti-fibrotic miRNA that suppresses cardiac fibrosis and improves the impaired cardiac function in post-infarct rats, which involves the

underlying mechanism of inhibiting the c-Fos/TGF|1 and TGF|R1 pathways [76, 77]. MiR-24 was also down-regulated in mouse heart after MI. MiR-24 improved heart function and attenuated fibrosis in the infarct border zone of the heart 2 weeks after MI induced through intramyocardial injection of lentiviruses, which was related to the regulation of furin (a protease that controls latent TGF| activation) and reduced TGF| (a pathological mediator of fibrotic disease) secretion and Smad2/3 phosphorylation in cardiac fibroblasts [78]. Moreover, up-regulating miR-711 inhibited cardiac fibrosis in rats with MI, which was mainly related to the reduced COLI levels [79]. Therefore, these miRNAs act as regulators of cardiac fibrosis and represent potential therapeutic targets of tissue fibrosis after AMI.

Recently, lncRNAs were also studied in cardiac fibrosis after AMI. A recent study detected lncRNAs variation in mice 4 weeks after MI and found that at the peri-infarct region, 53 lncRNAs had been up-regulated by more than twofold and 37 lncRNAs has been down-regulated by over 0.5-fold. Meanwhile, NONMMUT022554 was identified as the most significantly up-regulated lncRNA and was positively correlated with six up-regulated genes involved in ECM-receptor interactions [80]. Furthermore, some lncRNAs were also related to cardiac fibrosis. For example, overexpression of H19 contributed to cardiac fibroblast proliferation and fibrosis [81]. LncRNA cardiac hypertrophy-related factor also regulates cardiac hypertrophy [82]. However, the pro-fibrotic function of these lncRNAs in MI has not been identified, and with further exploration, they may also be potential targets for treating AMI.

LncRNA/circRNA-miRNA-mediated interaction

Generally, miRNAs bind directly to their target mRNAs by complementary base pairing and trigger mRNA cleavage based on the degree of complementarity. MiRNAs regulate gene expression, mostly at the 3' untranslated region, thereby decreasing mRNA translation and stability [83]. LncRNAs and circRNAs function as molecular regulators by determining gene expression from transcription to translation. More interestingly, lncRNAs and circRNAs both contain complementary binding sites to miRNAs and act as endogenous miRNA sponges; miRNAs in turn interact with mRNAs, serving as negative regulators of protein expression. Moreover, the regulatory mechanism of lncRNAs and circRNAs mainly focuses on acting as molecular sponges by binding to miRNAs and forming an lncRNA/circRNAs-miRNA axis to regulate the expression of the related mRNAs and proteins [9].

As previously reported, CARL induces cardiac myocyte apoptosis by acting as an endogenous sponge and reducing miR-539 levels, which subsequently inhibits mitochondrial fission and apoptosis in the heart [45]. H19 binds directly to miR-103/107, repressing RIPK1 and RIPK3, negatively regulating FADD and reducing apoptosis [46]. Similarly, MIAT acts as a competing endogenous RNA sponge to miR-150-5p, regulating VEGF levels and endothelial cell function [69]. The circRNA CDR1as functioned as a miR-7a sponge in myocardial cells and regulated cardiomyocyte apoptosis after MI [49]. These findings demonstrate the critical mechanism in the miRNA regulatory

networks, which are involved in the complex, competitive endogenous RNA network.

Conclusion and clinical perspectives

Recently, novel therapeutic approaches for AMI have received much attention, and numerous potential targets, especially ncRNAs, have been studied. Emerging data suggest that ncRNAs play important roles in several physiological and pathological processes in AMI. The best-studied ncRNAs are miRNAs; several miRNAs might be attractive candidates for improving recovery by controlling the pathological conditions of AMI. For example, several animal studies have demonstrated that miR-92a inhibitors reduce cardiomyocyte apoptosis and promote angiogenesis, thereby decreasing infarct size and improving prognosis after AMI. Apart from miRNAs, lncRNAs and circRNAs such as MIAT and CDR1as have emerged as potential regulators of AMI progression. However, these recently identified ncRNAs in AMI and their interactions have not been completely described. We analysed the ncRNAs implicated in the processes of AMI to gain insight into their potential functions as therapeutic targets of AMI.

Although the evidence is convincing and indicates that manipulating ncRNA levels is efficient for reducing infarct area and for restoring left ventricular mass, as well as promoting functional recovery after AMI in animal models, the development of ncRNA therapy faces several challenges. Moreover, it is difficult to use the regulatory ncRNAs in the clinic in a short time. First, our understanding of the biology of ncRNAs is far from complete; this is especially true for lncRNAs and circRNAs, which are involved in more complex and wider functions by interacting with miRNAs. Next, targeting ubiquitously expressed ncRNAs may encounter challenges with respect to off-target effects and unwanted adverse effects in other cells or tissues. In addition, as gene therapy requires the use of vectors to some extent, the safety and efficacy still requires thorough evaluation. Accordingly, although ncRNAs have promising application prospects, they have not reached the stage that would allow easy clinical translation. In future research, some cases may require cell type-specific delivery strategies. Preclinical trials (such as the antagomiR anti-miR-122 for treating hepatitis C virus infection [84, 85]) for evaluating their safety and feasibility will aid the development of ncRNA therapeutics for AMI.


This work was supported by the grant from the National Natural Science Foundation of China (No. 81372117). This work was supported by the Fundamental Research Funds for the Central Universities of Central South University (No. 2016zzts132).

Conflict of interest

The authors reported no relationships that could be construed as a conflict of interest.


1. Orogo AM, Gustafsson AB. Cell death in the 17.

myocardium: my heart won't go on. IUBMB Life. 2013; 65: 651-6.

2. Cochain C, Channon KM, Silvestre JS. Angiogenesis in the infarcted myocardium. Antioxid Redox Signal. 2013; 18:1100-13.

3. Mattick JS, Makunin IV. Non-coding RNA. 18. Hum Mol Genet. 2006; 15: R17-29.

4. Consortium IHGS. Finishing the euchromatic sequence of the human genome. Nature. 2004;431:931-45.

5. Wilusz JE, Sunwoo H, Spector DL. Long noncoding RNAs: functional surprises from

the RNA world. Genes Dev. 2009; 23:1494- 19. 504.

6. Doerks T, Copley RR, Schultz J, et al. Systematic identification of novel protein domain families associated with nuclear functions. Genome Res. 2002; 12: 47-56. 20.

7. Latronico MV, Catalucci D, Condorelli G. Emerging role of microRNAs in cardiovascular biology. Giro Res. 2007; 101:1225-36.

8. Bonauer A, Carmona G, Iwasaki M, et al. MicroRNA-92a controls angiogenesis and 21. functional recovery of ischemic tissues in mice. Science. 2009; 324:1710-3.

9. Wang KC, Chang HY. Molecular mecha- 22. nisms of long noncoding RNAs. Mol Gell. 2011; 43: 904-14.

10. Derrien T, Johnson R, Bussotti G, et al. The GENCODE v7 catalog of human long non-coding RNAs: analysis of their gene structure, evolution, and expression. Genome 23. Res. 2012; 22:1775-89.

11. Chen Y, Li C, Tan C, et al. Circular RNAs: a new frontier in the study of human diseases.

J Med Genet. 2016; 53: 359-65. 24.

12. Ebbesen KK, Kjems J, Hansen TB. Circular RNAs: identification, biogenesis and function. Bioohim Biophys Acta. 2016; 1859:163-8.

13. Liu LF, Liang Z, Lv ZR, etal. MicroRNA-15a/b are up-regulated in response to myocardial ischemia/reperfusion injury. J 25. Geriatr Gardiol. 2012; 9: 28-32.

14. Hullinger TG, Montgomery RL, Seto AG, et al. Inhibition of miR-15 protects against cardiac ischemic injury. Giro Res. 2012; 110: 26. 71-81.

15. Li X, Zeng Z, Li Q, et al. Inhibition of micro-RNA-497 ameliorates anoxia/reoxygenation injury in cardiomyocytes by suppressing cell apoptosis and enhancing autophagy. Onoo-target. 2015; 6:18829-44. 27.

16. Fiedler J, Jazbutyte V, Kirchmaier BC, et al. MicroRNA-24 regulates vascularity after myocardial infarction. Giroulation. 2011; 124: 720-30.

Meloni M, Marchetti M, Garner K, et al. 28.

Local inhibition of microRNA-24 improves reparative angiogenesis and left ventricle remodeling and function in mice with myocardial infarction. Mol Ther. 2013; 21: 1390-402.

Tony H, Meng K, Wu B, et al. MicroRNA- 29. 208a dysregulates apoptosis genes expression and promotes cardiomyocyte apoptosis during ischemia and its silencing improves cardiac function after myocardial infarction. Mediators Inflamm.2015; 2015: 479123. 30. DOI: 10.1155/2015/479123. Iekushi K, Seeger F, Assmus B, et al. Regulation of cardiac microRNAs by bone marrow mononuclear cell therapy in myocardial infarction. Circulation. 2012; 125:1765-73 , 31. S1-7.

Fan F, Sun A, Zhao H, et al. MicroRNA-34a promotes cardiomyocyte apoptosis post myocardial infarction through down-regulating aldehyde dehydrogenase 2. Curr Pharm 32. Des. 2013; 19: 4865-73. Wang K, Liu F, Zhou LY, et al. miR-874 regulates myocardial necrosis by targeting cas-pase-8. Cell Death Dis. 2013; 4: e709. Eisenhardt SU, Weiss JB, Smolka C, et al. 33. MicroRNA-155 aggravates ischemia-reperfu-sion injury by modulation of inflammatory cell recruitment and the respiratory oxidative burst. Basic Res Cardiol. 2015; 110: 32. 34. DOI: 10.1007/s00395-015-0490-9. Hu S, Huang M, Li Z, et al. MicroRNA-210 as a novel therapy for treatment of ischemic heart disease. Circulation. 2010; 122: S124- 35. 31.

Yang X, Qin Y, Shao S, et al. MicroRNA-214 inhibits left ventricular remodeling in an acute myocardial infarction rat model by 36. suppressing cellular apoptosis via the Phosphatase and Tensin Homolog (PTEN). Int Heart J. 2016; 57: 247-50. Glass C, Singla DK. ES cells overexpressing microRNA-1 attenuate apoptosis in the 37. injured myocardium. Mol Cell Biochem. 2011;357:135-41.

Glass C, Singla DK. MicroRNA-1 transfected embryonic stem cells enhance cardiac myo-cyte differentiation and inhibit apoptosis by modulating the PTEN/Akt pathway in the 38. infarcted heart. Am J Physiol Heart Circ Physiol. 2011; 301: H2038-49. Yang Q, Yang K, AY Li. Trimetazidine protects against hypoxia-reperfusion-induced cardiomyocyte apoptosis by increasing 39. microRNA-21 expression. Int J Clin Exp Pathol. 2015; 8: 3735-41.

Yang Q, Yang K, Li A. microRNA-21 protects against ischemia-reperfusion and hypoxia-reperfusion-induced cardiocyte apoptosis via the phosphatase and tensin homolog/ Akt-dependent mechanism. Mol Med Rep. 2014; 9: 2213-20.

Cheng Y, Zhu P, Yang J, et al. Ischaemic preconditioning-regulated miR-21 protects heart against ischaemia/reperfusion injury via anti-apoptosis through its target PDCD4. Cardiovasc Res. 2010; 87: 431-9. Cheng Y, Liu X, Zhang S, et al. MicroRNA-21 protects against the H(2)O(2)-induced injury on cardiac myocytes via its target gene PDCD4. J Mol Cell Cardiol. 2009; 47: 5-14.

Dong S, Cheng Y, Yang J, et al. MicroRNA expression signature and the role of micro-RNA-21 in the early phase of acute myocardial infarction. J Biol Chem. 2009; 284: 29514-25.

van Rooij E, Quiat D, Johnson BA, et al. A

family of microRNAs encoded by myosin genes governs myosin expression and muscle performance. Dev Cell. 2009; 17: 66273.

Chen X, Zhang L, Su T, et al. Kinetics of plasma microRNA-499 expression in acute myocardial infarction. J Thorac Dis. 2015; 7: 890-6.

Wang J, Jia Z, Zhang C, et al. miR-499 protects cardiomyocytes from H 20 2-induced apoptosis via its effects on Pdcd4 and PACS2. RNA Biol. 2014; 11: 339-50. Li Y, Lu J, Bao X, et al. MiR-499-5p protects cardiomyocytes against ischaemic injury via anti-apoptosis by targeting PDCD4. Oncotarget. 2016; 7: 35607-17. Dakhlallah D, Zhang J, Yu L, et al. Micro-RNA-133a engineered mesenchymal stem cells augment cardiac function and cell survival in the infarct heart. J Cardiovasc Pharmacol. 2015; 65: 241-51. Lu C, Wang X, Ha T, et al. Attenuation of cardiac dysfunction and remodeling of myocardial infarction by microRNA-130a are mediated by suppression of PTEN and activation of PI3K dependent signaling. J Mol Cell Cardiol. 2015; 89: 87-97. Ding SL, Wang JX, Jiao JQ, et al. A pre-microRNA-149 (miR-149) genetic variation affects miR-149 maturation and its ability to regulate the Puma protein in apoptosis. J Biol Chem. 2013; 288: 26865-77. Zhang Y, Sun L, Xuan L, et al. Reciprocal changes of circulating long non-coding rnas zfas1 and cdr1as predict acute

myocardial infarction. Sci Rep. 2016; 6: 52. 22384. DOI: 10.1038/srep22384.

40. Vausort M, Salgado-Somoza A, Zhang L, et al. Myocardial Infarction-Associated Circular RNA Predicting Left Ventricular Dysfunction. J Am Coll Cardiol. 2016; 68: 1247-8. 53.

41. Yan Y, Zhang B, Liu N, et al. Circulating long noncoding RNA UCA1 as a novel bio-marker of acute myocardial infarction. Biomed Res Int. 2016; 2016: 8079372. DOI: 10.1155/2016/8079372. 54.

42. Zangrando J, Zhang L, Vausort M, et al. Identification of candidate long non-coding RNAs in response to myocardial infarction. BMC Genom. 2014; 15: 460. 55.

43. Zhang J, Gao C, Meng M, et al. Long Non-coding RNAMHRT Protects Cardiomyocytes against H2O2-Induced Apoptosis. Biomol Ther (Seoul). 2016; 24:19-24.

44. Wang K, Liu CY, Zhou LY, et al. APFlncRNA 56. regulates autophagy and myocardial infarction by targeting miR-188-3p. Nat Commun. 2015; 6: 6779. DOI: 10.1038/ ncomms7779. 57.

45. Wang K, Long B, Zhou LY, et al. CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 down-regulation. Nat Commun. 2014; 5: 3596. DOI: 10.1038/ncomms4596. 58.

46. Wang JX, Zhang XJ, Li Q, et al. MicroRNA-103/107 regulate programmed necrosis and myocardial ischemia/reperfusion injury through targeting FADD. Circ Res. 2015; 59. 117: 352-63.

47. Wang K, Liu F, Liu CY, et al. The long noncoding RNA NRF regulates programmed necrosis and myocardial injury during ischemia and reperfusion by targeting 60. miR-873. Cell Death Differ. 2016; 23:1394405.

48. Memczak S, Jens M, Elefsinioti A, et al.

Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013; 61. 495: 333-8.

49. Geng HH, Li R, Su YM, et al. The Circular RNA Cdr1as promotes myocardial infarction by mediating the regulation of miR-7a on Its target genes expression. PLoS One. 2016;

11: e0151753. 62.

50. Sanders LN, Schoenhard JA, Saleh MA, et al. BMP antagonist gremlin 2 limits Inflammation after myocardial infarction. CircRes. 2016; 119: 434-49.

51. Liu Z, Ye P, Wang S, et al. MicroRNA-150 protects the heart from injury by inhibiting monocyte accumulation in a mouse model 63. of acute myocardial infarction. Circ Cardio-

vasc Genet. 2015; 8:11-20.

Yao R, Ma Y, Du Y, et al. The altered expression of inflammation-related micro-RNAs with microRNA-155 expression correlates with Th17 differentiation in patients 64. with acute coronary syndrome. Cell Mol Immunol. 2011; 8: 486-95. Liu X, Dong Y, Chen S, et al. Circulating MicroRNA-146a and MicroRNA-21 predict 65. left ventricular remodeling after ST-elevation myocardial infarction. Cardiology. 2015; 132: 233-41.

Ibrahim AG, Cheng K, Marban E. Exosomes as critical agents of cardiac regeneration 66. triggered by cell therapy. Stem Cell Reports. 2014; 2: 606-19.

Toldo S, Das A, Mezzaroma E, et al. Induction of microRNA-21 with exogenous hydrogen sulfide attenuates myocardial ischemic 67. and inflammatory injury in mice. Circ Cardio-vasc Genet. 2014; 7: 311-20. Vausort M, Wagner DR, Devaux Y. Long noncoding RNAs in patients with acute 68. myocardial infarction. Circ Res. 2014; 115: 668-77.

Bellera N, Barba I, Rodriguez-Sinovas A,

et al. Single intracoronary injection of encapsulated antagomir-92a promotes angiogenesis and prevents adverse infarct 69. remodeling. J Am Heart Assoc. 2014; 3: e000946.

Hinkel R, Penzkofer D, Zuhlke S, et al. Inhibition of microRNA-92a protects against 70. ischemia/reperfusion injury in a large-animal model. Circulation. 2013; 128:1066-75. Icli B, Wara AK, Moslehi J, et al. Micro-RNA-26a regulates pathological and physiological angiogenesis by targeting BMP/ 71. SMAD1 signaling. Circ Res. 2013; 113: 1231-41.

Kang HJ, Kang WS, Hong MH, et al.

Involvement of miR-34c in high glucose- 72. insulted mesenchymal stem cells leads to inefficient therapeutic effect on myocardial infarction. Cell Signal. 2015; 27: 2241-51. Garikipati VN, Krishnamurthy P, Verma SK, et al. Negative Regulation of miR-375 by 73. interleukin-10 enhances bone marrow-derived progenitor cell-mediated myocardial repair and function after myocardial infarction. Stem Cells. 2015; 33: 3519-29. Jakob P, Doerries C, Briand S, et al. Loss 74. of angiomiR-126 and 130a in angiogenic early outgrowth cells from patients with chronic heart failure: role for impaired in vivo neovascularization and cardiac repair capacity. Circulation. 2012; 126: 75. 2962-75.

Huang F, Zhu X, Hu XQ, et al. Mesenchymal stem cells modified with miR-126 release angiogenic factors and activate Notch ligand

Delta-like-4, enhancing ischemic angiogene-sis and cell survival. Int J Mol Med. 2013; 31:484-92.

Wang S, Aurora AB, Johnson BA, et al. The

endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. DevCell. 2008; 15: 261-71. van Mil A, Vrijsen KR, Goumans MJ, et al.

MicroRNA-1 enhances the angiogenic differentiation of human cardiomyocyte progenitor cells. J Mol Med (Berl). 2013; 91: 1001-12.

Bao MH, Feng X, Zhang YW, et al. Let-7 in cardiovascular diseases, heart development and cardiovascular differentiation from stem cells. Int J Mol Sci. 2013; 14: 23086102.

Chen Z, Lai TC, Jan YH, et al. Hypoxia-responsive miRNAs target argonaute 1 to promote angiogenesis. J Clin Invest. 2013; 123:1057-67.

Ghosh Goutam, Subramanian Indira V, Adhikari N, et al. Hypoxia-induced micro-RNA-424 expression in human endothelial cells regulates HIF-« isoforms and promotes angiogenesis. J Clin Investig. 2010; 120: 4141-54.

Yan B, Yao J, Liu JY, et al. lncRNA-MIAT regulates microvascular dysfunction by functioning as a competing endogenous RNA. CircRes. 2015;116:1143-56. Bernardo BC, Gao XM, Winbanks CE, et al. Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function. Proc Natl Acad Sci USA. 2012;109:17615-20. Huang Y, Qi Y, Du JQ, et al. MicroRNA-34a regulates cardiac fibrosis after myocardial infarction by targeting Smad4. Expert Opin Ther Targets. 2014; 18:1355-65. Shyu KG, Wang BW, Cheng WP, et al. MicroRNA-208a increases myocardial endo-glin expression and myocardial fibrosis in acute myocardial infarction. Can J Cardiol. 2015;31:679-90.

Liang H, Zhang C, Ban T, et al. A novel reciprocal loop between microRNA-21 and TGFbetaRIII is involved in cardiac fibro-sis. Int J Biochem Cell Biol. 2012; 44: 2152-60.

van Rooij E, Sutherland LB, Thatcher JE,

et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci USA. 2008; 105:13027-32. Melo SF, Fernandes T, Barauna VG, et al. Expression of MicroRNA-29 and Collagen in Cardiac Muscle after Swimming Training in Myocardial-Infarcted Rats. Cell Physiol Biochem. 2014; 33: 657-69.

76. Pan Z, Sun X, Shan H, et al. MicroRNA-101 inhibited postinfarct cardiac fibrosis

and improved left ventricular compliance 79. via the FBJ osteosarcoma oncogene/ transforming growth factor-beta1 pathway. Giroulation. 2012; 126: 84050. 80.

77. Zhao X, Wang K, Liao Y, et al. MicroRNA-101a inhibits cardiac fibrosis induced by hypoxia via targeting TGFbetaRI on cardiac fibroblasts. Gell Physiol Bioohem. 2015; 35: 81. 213-26.

78. Wang J, Huang W, Xu R, et al. MicroRNA-24 regulates cardiac fibrosis after myocar-

dial infarction. J Cell Mol Med. 2012; 16: 2150-60.

Zhao N, Yu H, Yu H, et al. MiRNA-711-SP1-collagen-I pathway is involved in the anti-fibro-tic effect of pioglitazone in myocardial infarction. Sci China Life Sci. 2013; 56:431-9. Qu X, Song X, Yuan W, et al. Expression signature of lncRNAs and their potential roles in cardiac fibrosis of post-infarct mice. Biosci Rep. 2016; 36: pii:e00337. Tao H, Cao W, Yang JJ, et al. Long noncod-ing RNA H19 controls DUSP5/ERK1/2 axis in cardiac fibroblast proliferation and fibrosis. Cardiovasc Pathol. 2016; 25: 381-9.

82. Wang K, Liu F, Zhou LY, et al. The

long noncoding RNA CHRF regulates cardiac hypertrophy by targeting miR-489. Giro Res. 2014;114:1377-88.

83. Bartel DP. MicroRNAs Target Recognition and Regulatory Functions. Gell. 2009; 136: 215-33.

84. Janssen HL, Reesink HW, Lawitz EJ, et al.

Treatment of HCV infection by targeting micro-RNA. N Engl J Med. 2013; 368:1685-94.

85. van der Ree MH, van der Meer AJ, de Brui-

jne J, et al. Long-term safety and efficacy of microRNA-targeted therapy in chronic hepatitis C patients. Antiviral Res. 2014; 111: 53-9.