The role of MicroRNAs on endoplasmic reticulum stress in myocardial ischemia and cardiac hypertrophy

Journal Pre-proof The Role of MicroRNAs on Endoplasmic Reticulum Stress in Myocardial Ischemia and Cardiac Hypertrophy Navid Omidkhoda, A. Wallace Hayes, Russel Reiter, Gholamreza Karimi

PII:

S1043-6618(19)31391-X

DOI:

https://doi.org/10.1016/j.phrs.2019.104516

Reference:

YPHRS 104516

To appear in:

Pharmacological Research

Received Date:

16 July 2019

Revised Date:

12 September 2019

Accepted Date:

29 October 2019

Please cite this article as: Omidkhoda N, Wallace Hayes A, Reiter R, Karimi G, The Role of MicroRNAs on Endoplasmic Reticulum Stress in Myocardial Ischemia and Cardiac Hypertrophy, Pharmacological Research (2019), doi: https://doi.org/10.1016/j.phrs.2019.104516

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The Role of MicroRNAs on Endoplasmic Reticulum Stress in Myocardial Ischemia and Cardiac Hypertrophy Navid Omidkhoda 1,2, A. Wallace Hayes3, Russel Reiter 4, Gholamreza Karimi 1,2*

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Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical

Sciences, Mashhad, Iran Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical

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2

Sciences, Mashhad, Iran

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University of South Florida, Tampa, FL USA and Michigan State University, East Lansing, MI, USA University of Texas, Health Science Center at San Antonio, Department of Cellular and Structural

Biology, USA.

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* Correspondence to: Gholamreza Karimi (Pharm D. PhD)

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Sciences, Mashhad, Iran Tel: +98513 8823255

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Fax: +98 5138823251

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Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical

E-mail address: [email protected]

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Graphical abstract

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Abstract

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The endoplasmic reticulum (ER) is the site of production and folding of secreted, membrane bound and some organelle targeted proteins. Accumulation of misfolded or unfolded proteins in the ER makes cells undergo a stress response known as the unfolded protein response (UPR). UPR is initially protective. However, prolonged and severe ER stress can lead to the induction of apoptosis in stressed cells. Cardiac hypertrophy and myocardial ischemia accounts for substantial morbidity and mortality worldwide. Accumulating evidence suggests that aberrant cardiac cell death caused by ER stress is often associated with structural or functional cardiac abnormalities. MicroRNAs (miRNAs) are a class of small non-coding RNAs that mediate posttranscriptional gene silencing. The miRNAs play important roles in regulating 2

cardiac physiological and pathological events such as hypertrophy, apoptosis, and heart failure. In this review, we discussed the role of microRNAs on Endoplasmic Reticulum Stress in myocardial ischemia and cardiac hypertrophy to demonstrate the relation between microRNAs and the ER in cardiac cells providing potential new treatment strategies and improvement of survival.

Abbreviations ACHD, acyanotic congenital heart defects; ATF6, Activating transcription factor 6; CCHD, Cyanotic congenital heart defects; CHOP, C/EBP homologous protein; CRT, Calreticulin; CTGF, connective tissue

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growth factor; eIF2α, eukaryotic initiation factor 2α; ER, Endoplasmic reticulum; ERAD, Endoplasmic reticulum associated degradation; ERK1/2, extracellular regulated kinase ½; Ero1, ER oxidoreductin1;

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GADD153, growth arrest and DNA damage inducible gene 153; GRP78, Glucose-regulated protein 78; HF, Heart failure; HIF-1α, Hypoxia-inducible factor-1α; HSP90, Heat shock 70kDa protein 90; I/R,

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ischemia/reperfusion; IHD, Ischemic Heart Disease; IL, interleukin; IRE1, inositol-requiring enzyme 1; JNK, c-Jun N-terminal kinase; LDH, lactate dehydrogenase; MAPK, mitogen activated protein kinase; MCP1, Monocyte chemoattractant protein 1; MDA, malondialdehyde; MI, Myocardial infraction; NCMs,

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neonatal cardiomyocytes; NF‐ κB, nuclear factor kappa B; OXPHOS, oxidative phosphorylation; PERK, protein kinase-like ER kinase; PPARγ, peroxisome proliferator-activated receptor gamma; PTEN,

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phosphatase and tensin homolog; RAAS, Renin–angiotensin–aldosterone system; ROS, Reactive oxygen species; Sig-1R, sigma-1 receptor; SIRT, Sirtuin; STAT3, Signal transducer and activator of transcription 3; TAC, transverse aortic constriction; TM, Tunicamycin; TSP-1, thrombospondin-1; UPR, unfolded

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protein response; UTR, untranslated region ; VEGF, vascular endothelial growth factor; XBP1, X-box binding protein

Key words: Endoplasmic reticulum stress, MicroRNA, Myocardial ischemia, Cardiac hypertrophy

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1. Introduction

The place of making and assembling of many secreted and essential proteins in the cell is the endoplasmic reticulum (ER) [1]. There are three mechanisms of the ER lumen that check the correct folding of these secretory and transmembrane proteins: (1) an oxidative condition for disulfide bond formation; (2) abundant chaperone proteins for protein folding; and (3) a high Ca2+ concentration favoring Ca2+dependent chaperone-protein interaction [2]. Many of cellular stress situations can activate accumulation

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of unfolded or misfolded proteins in the ER lumen, creating a threating condition to cellular integrity. Such condition in the ER triggers an unfolded protein response (UPR) to mediate cell survival. The UPR develops its function by initiating transcription of genes encoding ER-resident chaperones to simplify protein folding, decreasing translation to attenuate the requirements of the organelle, and ER-associated degradation (ERAD) to eliminate the unfolded proteins accumulated in the ER [3]. UPR is promoted by activation of three upstream signaling proteins including inositol requiring (IRE) 1α, PKR-like ER kinase (PERK), and activating transcription factor (ATF) 6α [4]. Traditionally, the most basic role of UPR in the cell is the maintenance of homeostasis. The importance of UPR in organ homeostasis is manifested by its rampant

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role in many diseases such as cancer, diabetes, neurodegenerative disorders and heart diseases [5]. For example, it is demonstrated that MI/R injury could lead to accumulation of misfolded/unfolded proteins in

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the ER that in prolonged stress conditions, eventually results in cell death. Thus, alleviating ER stress make a contribution to find new therapeutic strategy for treating I/R injury [6].

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MicroRNA (miRNAs) is implicated in plenty of physiological processes [7]. As in the case of highly conserved, short-non-coding RNAs (21-25 nucleotide in length), miRNAs by binding to the 3' untranslated

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region (3'-UTR) of the target mRNA at the post-transcriptional level, inhibit gene expression, leading to degradation of transcription repression [8]. These miRNAs target potentially hundreds of mRNAs and posttranscriptionally control multiple complex cellular functions including proliferation, differentiation, and

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apoptosis [9]. It has been observed that microRNAs have a substantial effect on the pro-adaptive/proapoptotic molecular switch originate from the ER. Specially, select miRNAs have been indicated to directly stimulate UPR response [10]. For example, miRNAs involved in the IRE1 branch of the UPR show anti-

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apoptotic properties, while those involved with either the PERK or the ATF6 branch illustrate more balanced effects. Interestingly, there are many miRNAs that appear as both modulators and effectors of UPR [5].

Cardiovascular diseases are major health challenges and remain the leading cause of worldwide death [11]. Patients with cardiovascular disease eventually progress to heart failure (HF) or myocardial infarction (MI).

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Despite numerous causative factors, the overwhelming majority of HF and MI cases are the consequences of massive cardiomyocytes loss [12]. Cardiomyocytes due to their poor replication are very susceptible to ER stress and affiliated to transmembrane proteins, such as ion channels for contractile processes. Hypertension and over load of Pressure or myocardial ischemia mostly results in an oxidative stress, energy deprivation, disordered calcium content, and inflammation which can disrupt ER folding and induce ER stress [13]. The aim of this paper is to review the role of microRNAs on endoplasmic reticulum stress in cardiac cells in order to shed addition light on these critical conditions.

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2. The relation between MicroRNAs and the ER 2.1. The relation between MicroRNAs and the ER in myocardial ischemia/ reperfusion (I/R)

Myocardial ischemia/ reperfusion (I/R) injury lead to harmful cardiovascular consequences after MI, heart surgery or circulatory arrest which in turn, illustrate a great cause of morbidity in patients who have coronary heart disease[14]. In myocardial I/R several complicated mechanisms have been proposed such 2+

as oxidative stress, overload of intracellular Ca , quick restoration of physiological pH in reperfusion,

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mitochondrial permeability transition pore, and excessive inflammation [15].

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2.1.1. MicroRNA-93/ phosphatase and tensin homolog (PTEN)

Lately, it has emerged that miRNAs have a fundamental effect in myocardial I/R injury and in consequence bring striking aims for therapeutic intervention [16]. MiRNAs perform their function through degradation

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or decrease translation of mRNAs at the post-transcriptional level [17]. PTEN which characterized as an antitumor gene, is a substantial regulator of cell functions such as replication, apoptosis, differentiation and

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migration. Lately, many researches have demonstrated that PTEN has a significant role in cardiac hypertrophy, myocardial fibrosis, and myocardial ischemia-reperfusion injury. Build upon bioinformatics

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studies, PTEN was recognized as a target of miR-93. After 10 h of hypoxia and 2.5 h reoxygenation the expression of miR-93 was attenuated 48% in comparison with control groups. Thus, miR- 93 seems to be an I/R-related miRNA in cardiomyocytes. Ke et al. reported that overexpression of miR-93 significantly attenuated H/R-induced lactate dehydrogenase (LDH) release, malondialdehyde (MDA) contents, reactive

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oxygen species (ROS) generation, and cell apoptosis in vitro [18]. Signaling pathways such as GRP78, CHOP, and caspase-12 are characterized as ER stress-associated apoptosis mediators [19, 20]. Also, it has been found that the levels of GRP78, CHOP, and caspase-12 were enhanced by I/R injury, while pretreatment of miR-93 negatively inhibited these effects. Thus, it is possible that the overexpression of miR-93 leads to decreasing ER stress-associated apoptosis and protecting cardiomyocytes during I/R injury

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[18].

PI3K/Akt is an intracellular signaling pathway that is involved in cardioprotection either [21]. PI3K can phosphorylate PIP2 to secondary messenger PIP3 and results in activating Akt. It may activate Akt and makes its prosurvival effect via the phosphorylation of two groups of downstream substrates: the prosurvival substrates and the proapoptotic substrates [22]. In addition, PTEN inhibits the PI3K/Akt pathway [23]. MiR-93 can attenuate cardiomyocytes apoptosis activated by I/R via suppression of PTEN

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and elevating nuclear Akt. It is hypothesized that miR-93 ameliorates I/R-induced cardiomyocyte

apoptosis by inhibiting PI3K/AKT/PTEN signaling [18].

2.1.2. MicroRNA-133a / Hydrogen Sulfide

Myocardial I/R injury is an intense cellular damage associated with cardiomyocyte apoptosis [24]. It has

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been shown that ischemic cells operate the ER stress response [25]. Cell and its organelles need to ER stress survival and protein production; nonetheless, a prolonged elevation to ER stress results in cell death

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[26]. Hydrogen sulfide (H2S) is a gaseous mediator that causes I/R-induced apoptosis inhibiting along with attenuating the myocardial infarct size [27]. MiR-133a has been indicated a protective effect on cardiac

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remodeling and antihypertrophic effect in cardiomyocytes as well [28]. The miR-133a expression was decreased after I/R injury, while overexpression of miR-133a could represent the opposite outcome. Also, H2S can reverse I/R-induced apoptosis and ER stress [29]. The levels of serum LDH were significantly

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elevated in the I/R group in comparison with the levels in the I/R + H2S + miR-133a mimic group as well. The results suggested that H2S and miR-133a protected the myocardium and improved cardiomyocyte

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contractility. It has also been found that the co-treatment of H2S and miR-133a was more effective than treatment by either candidate separately. The results suggested that the expression level of miR-133a may be regulated by H2S in cardiomyocytes. These findings support the hypothesis that co-treatment of H2S

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with miR-133a activator in H9C2 cells significantly decreases the I/R-induced ER stress and cardiomyocyte apoptosis results in enhanced cellular survival. These findings provide a new perspective into the potential of H2S and the miR-133a activator in protecting of cardiomyocytes in IHD [30].

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2.1.3. MicroRNA-711/ PPARγ / Calnexin

Since there is a weak clinical prognosis for cardiac remodeling which causes cardiac hypertrophy and interstitial fibrosis after myocardial infarction, it seems to be essential to find the details of pathways involved in the enlargement of cardiac cells and expand impressive treatment approaches [31]. Recently, it has been confirmed that peroxisome proliferator-activated receptor gamma (PPARγ) regulates MiR-711 in adipose cells [32]. It is found that PPARγ increases mir-711 via binding directly to the pre-miR-711 activator. In addition, miR-711 was speculated to act as an inhibitor of calnexin and calnexin blocking is characterized as an ER stress inducer. Treatment with a PPARγ ligand, pioglitazone, led to an upregulation 6

of miR-711 that causes ER stress-mediated cardiomyocyte apoptosis through targeting calnexin after MI. MiR-711 stimulated apoptosis via calnexin through eliminating its mRNA. moreover, GRP78, ATF6, and spliced XBP1 were increased by miR-711 which provoked that miR-711 promoted the UPR. Eventually, the level of ER-stress-mediated apoptotic mediators such as ASK1, CHOP, caspase 12, and ERO1a was increased by miR-711. In conclusion, this study propose that miR-711 has a substantial effect in regulating ER stress-mediated apoptosis and can be a new treatment target for cardiac remodeling in the primary stages

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after MI [33].

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2.1.4. MicroRNA-199a-5p / GRP78 / ATF6

Congenital heart defects happen in almost one percent of newborn children and can be classified into two categorize: cyanotic congenital heart defects (CCHD) and acyanotic congenital heart defects (ACHD) [34].

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Some heart structural deficiencies, such as tetralogy of Fallot, develop deoxygenated blood bypassing the pulmonary circulation which causes cyanosis in patients with CCHD [35]. Hearts in patient with CCHD

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consistently work with hypoxic blood. In spite of that, heart failure hardly happens in newborn children with CCHD who can remain alive for a while by withstanding the hypoxic-ischemic condition provoked by cardiac surgery [36]. The abnormity of energy metabolism affected by inadequate oxygen can affect ER

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protein folding in a negative fashion and trigger ER stress which leads to cell apoptosis [37]. It has been demonstrated that the UPR was elevated in myocardiocytes of patients with chronic hypoxic CCHD. The glucose-regulated protein (GRP78) level which is a main marker and molecular chaperone of UPR, were

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upregulated in cyanotic patients. Furthermore, the activating transcription factor 6 (ATF6) pathway, a major sensor of ER stress, was greatly stimulated in CCHDs patients [38]. Many studies have shown that MiRNA-199a-5p (miR-199a-5p) is the most expressed miRNA in the myocardium [39]. The downregulation of miR-199a-5p has been shown to help in avoiding cardiac hypertrophy and subsequent heart failure [40]. Many studies report that miR-199a-5p is susceptible to oxygen tension and the levels of

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miR-199a-5p are reduced quickly subsequent hypoxia. Hypoxia-inducible factor-1α (HIF-1α) is an authenticated aim of miR-199a-5p in different cells [41]. It has been found that miR-199a-5p regulates UPR stimulation via controlling GRP78 and ATF6 to protect CCHD patient’s cardiomyocytes along with chronic hypoxia. It might be that in normoxic conditions miR-199a-5p can enforce repression of GRP78 and ATF6 to basal expression. In contrast, under hypoxic conditions, the attenuation of miR-199a-5p partially reversed this effect, leading to an upregulation in GRP78 and ATF6 genes which provide myocardial survival. In summary, these results suggest new protection conduct of cardiomyocytes under chronic hypoxia in patients

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with CCHD. It is hypothesized that miR-199a-5p may be a new and useful target for the conservation of cardiomyocytes against hypoxia [42].

2.1.5. MicroRNA199a-5p / STAT3 Pathway

A lot of researches reported that the expression of target miR-199a-5p genes at post-transcriptional level was triggered through decreasing the level of miR-199a-5p in hypoxic myocardium, for instance, the

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hypoxia inducible factor (HIF), the vascular endothelial growth factor (VEGF), and Sirtuin (SIRT) which play a protective role for hypoxic ischemic myocardium by regulating myocardial oxygen metabolism and cardiac angiogenesis [43, 44]. It has been observed that inflammatory and anti-inflammatory reactions such

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as complement activation and NF-κB signal producing large number of cytokines, including interleukin (IL)-1β, IL-6, TNFα and the monocyte chemoattractant protein (MCP) 1 which increase in hypoxic

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myocardial through accumulation of reactive oxygen metabolites and toxic free radicals [45, 46]. Despite many inflammatory factors that caused myocardial cells damage, several cytokines such as IL-6 and IL-11

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have shown anti-inflammatory effects on myocardial cells, as a result, reducing myocardial hypertrophy and fibrosis, and preventing myocardial cell apoptosis. Generally, activation of the signal transducer and activator of the transcription 3 (STAT3) signal is the key for protective effects of these cytokines [47, 48].

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Several researches have emerged that some cardiovascular-related drugs such as rapamycin impact their therapeutic effect by activating STAT3 [49]. The precursor of miR-199a-5p, pri-miR-199a is encoded by the miR-199a-1 and miR-199a-2 genes [50]. It has been found through repressing the expression of miR-

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199a-2, hypoxia attenuated the level of miR-199a-5p in myocardial cells. The binding capacity of STAT3 to the miR-199a-2 promoter has been confirmed by the ChIP assay [51]. Finally, it has been observed that prolonged hypoxic condition could decrease miR-199a-5p levels by activating the STAT3 pathway. Attenuating miR-199a-5p promoted the expression of GRP78 and ATF6, the two major ER stress sensors and UPR effectors, thus benefiting the UPR process. The overall process results in the protection of

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cardiomyocytes against ER stress-related apoptosis. This is also a new survival mechanism of cardiomyocytes during hypoxic condition [52].

2.1.6. MicroRNA-7a / ATF4 / CHOP

There are three proteins in ER transmembrane of mammalian cells including IRE1, ATF6, and PERK which respond to stress conditions such as accumulating of unfolded proteins in the ER lumen [53]. ER proteins respond, trigger a signaling cascades from ER to nucleus that called UPR. PERK regulated phosphorylation 8

of eukaryotic translation initiation factor 2 on the alpha subunit (eIF2α) at Ser51 results in decreasing of translational level [54]. Despite that, phosphorylation of eIF2α enforces the general translation inhibition, it inversely elevate the translation of activating transcription factor 4 (ATF4) which facilitates homeostasis restoration by inducing transcription of related genes [55]. During ER stress conditions, BIM (a proapoptotic member of the BCL-2 family) expression, transcriptionally upregulated by C/EBP homologous protein (CHOP) that operates a substantial role in downstream of the ER stress pathway [56]. Therefore, the UPR facilitates the ER homeostasis restoration, however, apoptosis occurs in prolonged stress conditions [1].

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It has been illustrated that ischemic conditions interrupt ER homeostasis and cause the UPR activation [57]. This respond contributes to the progress of ischemic heart defects and increasing morbidity [58]. Several

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line of studies suggests that miRNAs have an substantial effects on heart disease [59]. Multiple miRNAs have been involved in the regulation of cardiac apoptosis and fibrosis in consequence of myocardial ischemia [60]. Recently, it has been observed that in mediated in vitro ischemia in cardiomyoblasts the

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expression of miR-7a was elevated by UPR. Moreover, the improper expression of miR-7a developed resistance against UPR-induced apoptosis in cardiomyoblasts [61]. The activation of the ATF4-CHOP

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signaling pathway mediated by miR-7a expression during UPR. It is reported that the overexpression of CHOP triggers pro-apoptotic signals in cells, but CHOP-deficient cells were unaffected by ER stressinduced apoptosis [62]. These results suggested that miR-7a have a protective effect against CHOP and

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provides resistance to ER stress-induced cell death. However, no sites have been found for miR-7a in the 3’ UTR of ATF4 or CHOP. Therefore, the effect of miR-7a on the induction of ATF4 and CHOP is most

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probably indirect. In conclusion, miR-7a may be a novel treatment target for cardiac ischemic diseases [61].

2.2. The relation between MicroRNAs and ER in cardiac hypertrophy

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Cardiac hypertrophy manifests itself as larger myocardial cells which leads to deterioration of cardiac pump function and increases the risk of cardiovascular diseases such as heart failure, coronary atherosclerotic and cardiac arrest. It is triggered as an adaptive reaction to sustained overload which has demolishing outcomes that ends up to heart failure and loosing of patients [63].

2.2.1. MicroRNA-124 / Angiotensin II

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Multiple mechanisms concerning cardiac hypertrophy have been suggested. The renin–angiotensin– aldosterone system (RAAS) is an remarkable compensatory mechanism to maintain cardiac output by increasing blood pressure, fluid volume, peripheral arterial vasoconstriction and by activating some inflammatory factors [64]. Several researches have illustrated that AngII disturbed the balance of the ER [65, 66]. Also, it has been reported that miRNAs, such as miR-455, miR-19a/b, and miR-30 promoted or attenuated cardiac hypertrophy via regulating ER stress [67-69]. MiR-124 regulated bone marrow-derived mesenchymal stem cells to differentiate cardiomyocytes via targeting signal transducer and activator of transcription (STAT3) signaling [70]. It is speculated that miR-124 participates in myocardial hypertrophy

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induced by AngII because it has been observed that miR-124 was markedly elevated in AngII-induced myocardial hypertrophy. Additionally, overexpression of miR-124 efficiently increased the mRNA level of

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ANP, BNP, and β-MHC and the cell surface area of neonatal cardiomyocytes (NCMs) in the presence of AngII, whereas knockdown of miR-124 notably inhibited the hypertrophic response induced by AngII. Taken together, it appears that miR-124 may exacerbate AngII-induced cardiac hypertrophy. In addition, it

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has been reported that forced expression or inhibition of miR- 124 can influence the expression of Grp78 and CRT, two ER stress markers, in hypertrophic cardiomyocytes. These data suggest that miR-124

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promoted myocardial hypertrophy partly via activation of ER stress in NCMs exposed to AngII stimulation. However, further studies are necessary to determine the target gene of miR-124 in hypertrophic cardiomyocytes. In conclusion, these findings strongly suggest that miR- 124 inhibition effectively

ER stress [71].

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suppresses AngII-induced myocardial hypertrophy and this action may be associated with attenuation of

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2.2.2. MicroRNA-297 / Sigma-1 receptor

Cardiac remodeling and hypertrophy is induced by overloading the pressure/volume or activation of neurohumoral systems such as the rennin-angiotensin system (RAS) and/or the β-adrenergic receptors [72, 73]. Several signaling pathways contribute to development of cardiac hypertrophy such as Ca2+ /calmodulin

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dependent kinase II signaling, the mitogen activated protein kinase (MAPK)-extracellular regulated kinase 1/2 (ERK1/2) pathway, and ER stress [74-76]. The most important pathway is ER stress because of its effect on cardiovascular diseases such as atherosclerosis, heart attack, and high blood pressure that ultimately result in heart failure [77, 78]. Recently, a research has indicated that ER stress induced the sigma-1 receptor (Sig-1R) expression through the PERK pathway [79]. Sig-1R is a ligand-regulated molecular chaperone, basically confined at the mitochondria-associated ER membrane (MAM), and has an interface role between the ER and the mitochondria [80]. Up-regulation of Sig-1R through the PERK/ATF4 pathway provides ER stress attenuation and cell survival [81]. It has been found that in the rat TAC heart 10

tissue and in NCMs the level of miR-297 was largely increased due to AngII stimulation which confirmed the substantial role of miR-297 in cardiac hypertrophy. In addition, it has been emerged that the expression of miR-297 was inhibited Sig-1R expression which could be one of the mechanisms of miR-297 in inducing cardiac hypertrophy [82]. It has been reported that up-regulation of PERK leading to heart failure in human induced pluripotent stem cell derived cardiomyocytes exposed to AngII [83]. Sig-1R via PERK/eIF2a/ATF4 pathways represents inhibiting impress on ER stress [81]. Thus, Qinxue et al. determined the important factors of the PERK, IRE1α, and ATF6 pathways and indicated stimulation of two branches of UPR including Xbp1 splicing and ATF4 translation were greatly suppressed in AngII

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treated cardiomyocytes after knockdown of miR-297 [82]. IRE1α is a transmembrane Ser/Thr protein kinase with site-specific endoribonuclease activity that can splice Xbp1. The spliced Xbp1 (Xbp1s) is a key protein in ER stress signaling [84]. It has been observed that the level of Xbp1s is dependent on miR-297

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expression, offering Sig-1R could be mediator of the IRE1α/Xbp1 pathway. In conclusion, increasing the activation of the Xbp1 and ATF4 pathways through suppressing Sig-1R by up-regulation of miR-297

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promoted cardiomyocyte hypertrophy induced by AngII. These studies suggested that miR-297 is a novel regulator of Sig-1R in NCMs. Inhibition of its expression could be a promising target for treatment of

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cardiac hypertrophy [82].

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2.2.3. MicroRNA-19a/b family / Atrogin-1 / MuRF-1

MiR-19a and miR-19b (miR-19a/b) are located in the miR-17-92 cluster which encodes four other mature miRNAs, miR-17, miR-18a, miR-20a, and miR-92a [85]. In the heart, miR-19b has been suggested to be

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involved in aging-associated heart failure through inhibition of ECM (extracellular matrix)-related proteins such as CTGF (connective tissue growth factor), TSP-1 (thrombospondin-1), collagen1A1, and collagen 3A1 [86]. Recently, mice overexpressing the miR-17-92 cluster showed left ventricular dilation and spontaneous cardiac arrhythmia indicating the importance of this miRNA cluster in heart function [87]. Previously, endogenous expression of miR-19a and miR- 19b was reported to be up-regulated in TAC

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(transverse aortic constriction)-operated mice showing the phenotype of cardiac hypertrophy [88, 89]. Atrogin-1 is a muscle-specific F-box protein and has been shown to interact with CN at the Z-disc of cardiomyocytes. Overexpression of atrogin-1 inhibited CN phosphatase activity, CN-dependent nuclear translocation of NFATc4 and cardiac hypertrophy, whereas down-regulation of atrogin-1 resulted in the opposite effects such as increased phosphatase activity and cardiac hypertrophy. Modulation of atrogin-1 expression appears to be a leading factor contributing to CN/NFAT signaling and cardiac hypertrophy [90]. Down regulation of atrogin-1 by miR-19a/b was accompanied by induction of pro-hypertrophic type responses such as enhanced CN/NFAT activity [69]. MuRF-1 was also reported to prevent cardiac 11

hypertrophy through inhibition of PKCε, one of the well-known Ca2+ -dependent PKC isoforms and prohypertrophic signaling molecule [91]. The antihypertrophic role of MuRF-1 was also supported by the finding that miR-23a directly targeted MuRF-1 and induced cardiac hypertrophy [92]. Also, miR-19induced hypertrophy was attenuated by treatment with the PKC inhibitor GF109203X. Thus, MuRF-1 appears to act as a powerful antihypertrophic regulator and the miR-19-mediated dysregulation of MuRF1 may contribute to the pathogenesis of cardiac hypertrophy. The conserved miR-19-binding sites of MuRF1 and atrogin-1 in humans also suggested that miR-19 plays an important role in human cardiac pathology [69]. The αCryB gene which is known to be directly transcribed by both NFATc3 and NFATc4 [93] is the

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cardioprotective gene that mediates cell survival against ER-stress-induced apoptosis [94, 95]. It has been found that miR-19 increased the expression of αCryB during TG-induced ER stress. Thus, miR-19b

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appeared to have a beneficial effect on cardiomyocyte fate via activation of CN/NFAT and up-regulation of the survival gene [69]. It also has been observed that the Bcl-2-interacting mediator of cell death (Bim), the proapoptotic protein, was down-regulated by miR-19b in rat cardiomyocytes, suggesting that down-

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regulation of Bim could also contribute to the survival role of miR-19b under conditions of ER stress. It has been suggested that the miR-19a/b family regulated cardiac hypertrophy and survival through

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repression of the novel target genes atrogin-1 and MuRF-1 and the target gene Bim. Therefore, miR-19a/b induced changes of cardiac remodeling would be mediated by downstream signaling pathways of these

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target molecules [69].

2.2.4. MicroRNA-183-5p / AGGF1

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The pro-apoptotic transcriptional factor C/EBP homologous protein (CHOP) that also recognized as growth arrest and DNA damage inducible gene 153 (GADD153) is activated by ER stress [96-98]. Activating transcription factor 4 (ATF4) triggers transcriptional stimulation of CHOP, whilst during stress condition through elevation of eIF2α phosphorylation only particular mRNAs, such as the ATF4 and CHOP mRNA, are translated [99, 100]. Transcriptional activation of CHOP induced by ATF4 binding to the CHOP

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promoter directly [98]. Actually, the levels of CHOP affect reversely on ATF4 and phosphorylated eIF2α (p-eIF2α) via activating the transcription of the GADD34 gene encoding a regulatory subunit of the phosphatase for eIF2α [96, 101, 102]. The CHOP level was greatly elevated in cardiac hypertrophy and heart failure [98, 101]. While it has been reported that in CHOP knockout (KO) mice cardiac hypertrophy induced by pressure overload and apoptosis significantly attenuated [101]. The AGGF1 gene encodes an angiogenic factor with a G-patch domain and a Forkhead-associated domain (FHA) 1 and confers the risk of a congenital vascular disorder, Klippel-Trenaunay syndrome [103, 104]. Also, AGGF1 was necessary during zebrafish embryogenesis for differentiation of the multipotent 12

hemangioblasts [105] and determination of veins [106]. Also, AGGF1was crucial for early embryogenesis and vascular development, physiological and pathological angiogenesis and suppression of vascular permeability [107]. Most interestingly, AGGF1 treatment markedly increased cell survival and restored cardiac function in MI and I/R models [107, 108]. AGGF1 decreased CHOP expression through upregulation of miR-183-5p at a post-transcriptional level by binding to 3′-UTR of CHOP. It has been revealed that AGGF1 treatment inhibited cardiac hypertrophy and almost restored myocardial function (LVEF and LVFS) to normal levels by suppression of CHOP provoked apoptosis [109]. Fu et al. emerged inhibiting translation in Chop-deficient mice and also suppressing cardiac hypertrophy happen through elevation of

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eIF2α phosphorylation [101]. It has been indicated that AGGF1 reversely increase the phosphorylation of eIF2a by attenuation of CHOP level. Elevating the phosphorylation of eIF2α could be one of the major

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mechanisms causes inhibition of cardiac hypertrophy by AGGF1 which reduce protein synthesis. Also, miR-183-5p decreased cardiomyocytes apoptosis, attenuated cardiac hypertrophy and heart failure and restored myocardial function. Through miR-183-5p inhibitors analyses, AGGF1served as upstream of miR-

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183-5p in regulating cardiac hypertrophy and heart failure. Besides, AGGF1 inhibited ERK1/2 activation, reduced expression of ZEB1, and stimulated expression of miR-183-5p which then inhibited expression of

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CHOP, the key inducer of apoptosis [109]. Recent observations have shown that AGGF1 protein induced autophagy in HL1 and H9C2 cells and in the mouse heart [108]. On the other hand, AGGF1, by inducing autophagy, act as a cardiomyocytes protector against apoptosis and improve myocardial function. It seems

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that the key of inhibiting cardiac hypertrophy and heart failure is the combination of AGGF1 effects including induced autophagy and AGGF1-mediated ER stress signaling. In summary, AGGF1 protein treatment has a protective effect on cardiomyocytes due to suppression of ER

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stress which leads to inhibition of cardiac hypertrophy and heart failure. AGGF1 modulated ER stress signaling by a novel AGGF1-ERK-ZEB1-miR-183-CHOP signaling pathway. Thus, AGGF1 protein treatment can be a new and promising therapeutic approach for cardiac hypertrophy and heart failure [109].

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2.2.5. MicroRNA‐93 / HSP90 inhibitor 17‐AAG

Tunicamycin (TM) is a mixture of homologous nucleoside antibiotics that can block N‐ linked glycosylation. TM has been used to create in vitro apoptosis models by ER stress activating in cultured neonatal rat cardiomyocytes [110, 111]. Interestingly, it has been emerged that an HSP90` (heat shock protein 90) inhibitor, 17-AAG (tanespimycin), operates as a new apoptosis inhibitor in different kinds of cells [112-114]. The action of nuclear factor kappa B (NF‐ κB), can demonstrate the obscurity of cell signaling in regulation of apoptosis. NF‐ κB is a transcriptional complex that can be induced by ER stress in cardiomyocytes [115-117]. By phosphorylation and degradation of inhibitors such as IkBα, the primary 13

inhibitor of p65/p50, the complex is activated [118]. So then NF‐ κB goes to the nucleus to activate the expression of specific genes mediating processes including cell survival, apoptosis, inflammation, and antiviral responses [118-120]. It usually operates as a protective cardiovascular role under various stress conditions but under prolonged activation of NF‐ κB can contribute to pathogenesis by inducing cardiac cell death [117, 121]. It has been observed that 17‐ AAG can suppress TM‐ induced ER stress and NF‐ κB stimulation in neonatal rat cardiomyocytes, and finally reduce apoptosis. In this regard, it has been demonstrated that miR‐ 93 plays an downstream mediator role for 17‐ AAG to inhibit the apoptosis processes [122]. It has been provoked that 17‐ AAG pretreatment in cells with downregulated miR‐ 93has

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not previous respond; thus, it has been suggested that 17‐ AAG can be a cardiomyocytes protector under TM mediated stress conditions but its function is probably affiliated to the miR‐ 93–associated regulatory

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network. In conclusion, these results suggest a potential role of 17‐ AAG and miR-93 in supporting oncogenic signaling in cardiomyocytes which finally could improve cell survival under stress conditions

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2.2.6. MicroRNA-378 and MicroRNA-378*

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[122].

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MiR-378 and 378* are expressed in multiple kinds of cells. MiR-378 has been often characterized as an oncogene-like microRNA in several cancer cell lines [31, 123, 124]. Knock-out of miR 378 and miR-378* in mice leads to a resistance to high-fat diet-induced obesity, enhanced mitochondrial fatty acid metabolism,

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and elevated oxidative capacity of insulin-target tissues [125]. In cardiac cells the miR-378: miR-378* hairpin is largely expressed. It has been indicated through deep sequencing data that miR-378 is between the 20 most abundant microRNAs in the heart of various species [126, 127]. There is a common subset of physiological pathways for MiR-378 and miR-378* to regulate in cardiac cells including: glycolysis, cytoskeleton, and ER Ca2+ buffering and chaperone proteins [128]. Inhibition of transcriptional mediators

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of ERRγ and GABPA operated by overexpression of miR-378* in breast cancer cells and decreasing oxidative phosphorylation (OXPHOS) which indirectly made an elevation in the rate of glycolysis and LDHA activity. This metabolic modification, characterized as the Warburg effect which is particular to cancer cells [129]. It seems that miR 378 and miR-378* have an inhibiting role on LDHA expression in H9c2 cells, as well as approving the role of the effect of miR-378 hairpin in the balancing between glycolysis and lactate production and OXPHOS [128]. The expression of miR-378/378* hairpin enhances day by day after birth in the heart and it seems the abundance of miR-378 is more than miR-378* [130]. Also, it has been indicated that changes in protein expression in the repartition of cytoskeleton components 14

and mitochondria happen by a dysregulation in OXPHOS [131]. It has been suggested that the cytoskeleton disorganization depends on energy metabolism deficiency along with heart failure [132]. It has been shown that in cells which vimentin has been disrupted the movement of mitochondria largely elevated while primarily the majority of mitochondria were fixed at sites in the cytoplasm to provide local ATP [133]. In opposite, inhibiting of mitochondria complex IV made a deficiency in the vimentin network throughout the nucleus [131]. Polymerization of actin is also crucial for mitochondrial attachment [134]. Therefore, the impact of miR-378* on OXPHOS metabolism could be due to its direct targeting of vimentin and actin [129]. These data suggested that multiple proteins related to Ca2+ buffering such as calumenin and GRP78

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and chaperone activity such as PPIA and GRP78 can be inhibited by these miRs [128]. In cells low glucose levels triggers synthesis of GRP78 [135], a chaperone protein which known as a ER stress marker. GRP78

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also maintained cytoplasmic calcium homeostasis through mediating the Ca2+ flow of the ER which operates a crucial role in the controlling of mitochondria activity [136]. It has been demonstrated that miR378 Severely inhibited GRP78 while the miR-378* was a potent suppressor of PPIA expression [128]. In

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addition, GRP78 contributing to mitogenesis and cellular proliferation [136] which suggested that its inhibition by miR-378 along with LDHA inhibition suppressed cellular replication. In conclusion, these

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results supported the conclusion that miR-378 and miR-378* established a relation among energy metabolism, cytoskeleton remodeling, and ER function in cardiac cells by post-transcriptional regulation of key proteins involved in these pathways [128].

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{table 2}

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3. Conclusion and Future perspective

There are an increasing number of studies suggesting the importance of finding new strategies for cardiac diseases treatment. Since cardiac remodeling and myocardial ischemic is activated through ER stress, finding ways to repress ER stress could lead to novel therapeutic approaches. Based on several studies, microRNAs have numerous effects on ER. For instance, mir-93, mir-133a, mir-7a, mir183-5p, mir378, and

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mir378* agonists, and mir-199a-5p, mir-711, mir-124, and mir-297 antagonists appear to have the potential to be helpful in cardiac diseases treatment. We suggest that knowledge of such miRNAs functions will provide novel insight into the pathogenesis during cardiac remodeling and myocardial ischemia under stress conditions. {figure1}

Conflict of Interest 15

Authors declare no conflict of interest.

Acknowledgment The authors are thankful to Mashhad University of Medical Sciences, Iran.

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Figure 1. Schematic showing activation of the three arms of the unfolded protein response (UPR). The

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three ER stress sensors, PERK, IRE1, and AFT6, are maintained in their inactive state through interaction with the ER chaperone GRP78 (BiP). In response to accumulating misfolded/unfolded proteins in the ER, GRP78 dissociates from the luminal domain of these sensors, leading to their activation. The concerted action of PERK, IRE1, and AFT6 activates a transcriptional response which can be adaptive or apoptotic and is essential for cell survival during ER stress. MicroRNAs can affect these paths either positively or negatively.

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Table 1. The role of microRNAs on the Endoplasmic Reticulum Stress in Myocardial Ischemia Target

Biological function

Pathophysiological effects

Reference

MicroRNA-93

Increase

PTEN

Decrease ER stress

Protect cardiomyocytes during I/R injury

(16)

MicroRNA133a

Increase

_

Decrease ER stress

Protect cardiomyocytes during I/R injury

(28)

MicroRNA-711

Decrease

Calnexin

Decrease ER stress

Protect cardiomyocytes during I/R injury

(31)

MicroRNA199a-5p

Decrease

GRP78 , AFT6

Decrease ER stress

Protect cardiomyocytes during I/R injury

(50)

MicroRNA-7a

Increase

AFT4, CHOP

Decrease ER stress

Protect cardiomyocytes during I/R injury

(59)

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Expression

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MicroRNA

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PTEN, phosphatase and tensin homolog; GRP78, Glucose-regulated protein 78; ATF6, Activating transcription factor 6; CHOP, C/EBP homologous protein;

Table 2. The role of microRNAs on the Endoplasmic Reticulum Stress in Cardiac Hypertrophy Expression

Target

Biological function

Pathophysiological effects

Reference

MicroRNA124

Decrease

AngII

Decrease ER stress

Inhibit myocardial hypertrophy

(69)

MicroRNA297

Decrease

Sigma-1R

Decrease ER stress

Inhibit myocardial hypertrophy

(80)

MicroRNA19a/b

Increase

Atrogin-1, MuRF1,Bim

Decrease ER stress

Inhibit myocardial hypertrophy

MicroRNA183-5p

Increase

CHOP

Decrease ER stress

MicroRNA‐93

Increase

NF‐κB

Decrease ER stress

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MicroRNA

(67)

(107)

Inhibit myocardial hypertrophy

(120)

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Inhibit myocardial hypertrophy

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Increase Calumenin, PPIA, Decrease ER Inhibit myocardial (126) MicroRNAGRP78 stress hypertrophy 378 MicroRNA378* AngII, Angiotensin II; Sigma-1R, Sigma-1receptor; CHOP, C/EBP homologous protein; NF‐ κB, nuclear factor kappa B; PPIA, cyclophilin A; GRP78, Glucose-regulated protein 78;

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