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Review

Functional Role of microRNAs in Regulating Cardiomyocyte Death

by
Urna Kansakar
1,†,
Fahimeh Varzideh
1,†,
Pasquale Mone
1,
Stanislovas S. Jankauskas
1,2 and
Gaetano Santulli
1,2,*
1
Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York, NY 10461, USA
2
Department of Molecular Pharmacology, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Fleischer Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, New York, NY 10461, USA
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2022, 11(6), 983; https://doi.org/10.3390/cells11060983
Submission received: 10 December 2021 / Revised: 8 March 2022 / Accepted: 9 March 2022 / Published: 12 March 2022
(This article belongs to the Special Issue Mechanisms of Ischemic Heart Injury)
Browse Figure
Review Reports Versions Notes

Abstract

:
microRNAs (miRNA, miRs) play crucial roles in cardiovascular disease regulating numerous processes, including inflammation, cell proliferation, angiogenesis, and cell death. Herein, we present an updated and comprehensive overview of the functional involvement of miRs in the regulation of cardiomyocyte death, a central event in acute myocardial infarction, ischemia/reperfusion, and heart failure. Specifically, in this systematic review we are focusing on necrosis, apoptosis, and autophagy.

1. Introduction

MicroRNAs (miRNAs, also known as miRs) are a group of small single-stranded noncoding RNA (ncRNA) with approximately 18–22 nucleotides; miRNAs regulate gene expression by binding to the 3′-untranslated region (3′UTR) of the messenger RNA (mRNA) of a target gene, enhancing its degradation and/or inhibiting protein translation [1,2,3].
Numerous studies have shown that miRNAs play essential roles in cardiovascular diseases regulating a plethora of processes including cell death, cell proliferation, inflammation, and angiogenesis [4]. In this review, we will focus on the involvement of miRNAs in the regulation of cardiomyocyte death.
Cardiomyocyte death is the central event in acute myocardial infarction; additionally, cell death has been shown to contribute significantly to the pathogenesis of ischemia/reperfusion and heart failure [5,6,7].

2. miRNAs and Cardiomyocyte Necrosis

Necrosis (from Ancient Greek νέκρωσις, nékrōsis, “death”) is a pathological process characterized by a gain in cell volume, swelling of organelles, lysis of plasma membrane, and leaking of intracellular content [8]. Necroptosis, mitochondrial permeability transition (MPT)-dependent necrosis, pyroptosis, ferroptosis, parthanatos, and NETosis are all different types of programmed necrosis [9,10].
Various investigations have shown that necroptosis and MPT-dependent necrosis are involved in the pathogenesis of myocardial infarction, ischemia/reperfusion, and heart failure [11,12]. Necroptosis is initiated by the binding of cytokines including tumor necrosis factor alpha (TNF-α), Fas/CD95, and TRAIL (TNF-related apoptosis-inducing ligand) to death receptors (e.g., TNFR1, TNFR2) and to active receptor interaction protein kinase 1 and 3 (RIP1 and RIP3), causing the formation of the necrosome [13,14].
Pei-feng Li’s research team was the first to report that miR-103/107 induces necrosis through targeting Fas-associated protein with death domain (FADD) in H2O2-treated H9c2 cardiomyoblasts and, in vivo, in a mouse model of ischemia/reperfusion; FADD inhibits necrosis by blocking the formation of the receptor-interacting serine/threonine protein kinase 1 and 3 (RIP1-RIP3) complex [15]. They also found that the long non-coding RNA H19 (lncRNA-H19), which contains three potential miR-103/107 binding sites, can attenuate cardiac necrosis by inhibiting miR-103/107 [15]. These results support a link among H19, miR-103/107, FADD, and RIPK1/RIPK3 in cardiomyocytes.
Another long non-coding RNA, namely necrosis-related factor (NRF), was shown to regulate necrosis in H2O2-treated cardiomyocytes and in mice challenged by ischemia/reperfusion through means of the repression of miR-873; this specific miR reduces necrosis by silencing the translation of RIPK1/RIPK3 [16]. Since NRF is also modulated by p53 [17], NRF overexpression by p53 can markedly aggravate myocardial necrosis [16]. Another study proved that lncRNA E2F1 increases cardiomyocyte necrosis by inhibiting miR-30b and cyclophilin D (CypD); in fact, miR-30b decreases necrosis and infarct size by targeting CypD [18].
miR-874 represents a perfect example of a miR that is mechanistically involved in cardiomyocyte necrosis experimentally induced by H2O2: its expression increases in H2O2-treated murine cardiomyocytes and its knockdown reduces necrosis in H2O2-treated cardiomyocytes and in a murine model of ischemia/reperfusion injury; caspase-8, which negatively affects myocardial necrosis by cleaving and inactivating RIP3 [19], was identified as a downstream target of miR-874 [20]; FOXO3a is known to repress miR-874 expression [21] and its overexpression attenuates cardiac necrosis [20].
In a mouse model of myocardial infarction, miR-325-3p overexpression was shown to suppress the expression of necrosis mediators including RIPK1, RIPK3, and phosphorylated mixed lineage kinase domain-like protein (p-MLKL) [22]. Reduced expression of lactate dehydrogenase (LDH), phosphocreatine kinase (CK), superoxide dismutase (SOD), and malondialdehyde (MDA), and increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVES) were observed by overexpressing miR-325-3p [22]. An increased expression of miR-155 was detected in cardiomyocyte progenitor cells when stressed with H2O2 [23]; miR-155 overexpression decreases necrotic cells through inhibiting RIP1 [23,24].
The downregulation of Adenine nucleotide translocase 1 (ANT1) is another mechanism underlying cardiomyocyte necrosis [25]; by directly targeting ANT1, miR-2861 was shown to induce necrotic cell death in hypoxia-treated murine cardiomyocytes, as well as in mice challenged by ischemia/reperfusion injury [26]; confirming these findings, knocking miR-2861 down preserved cardiomyocytes from necrosis via inhibition of ANT1 degradation [26].

3. miRNAs and Cardiomyocyte Apoptosis

Apoptosis (from Ancient Greek ἀπόπτωσις, apóptōsis, ‘falling off’) is a form of programmed death [27,28] that plays an important role in the pathogenesis of cardiovascular disorders [29,30,31,32]. In conditions such as myocardial infarction, apoptosis occurs in terminally differentiated cardiomyocytes and inhibition of apoptosis has been shown to protect the heart against ischemia/reperfusion injury [30,33].
The apoptosis machinery is activated by intrinsic mitochondrial pathway and extrinsic cell surface death receptor pathway and is characterized by a series of structural and morphological changes including chromatin condensation, DNA degradation, cell shrinkage, and blebbing of plasma membrane [34,35]. In the extrinsic pathway, extracellular ligands, such as tumor necrosis factor alpha (TNF-α) and FasL bind to the death receptor (e.g., Fas, TNFR) to activate intracellular caspases [36].
On the other hand, the intrinsic pathway is mainly mediated by mitochondria-associated BCL-2 family proteins, namely BAX and BAK [37,38,39,40,41,42], located in the outer mitochondrial membrane [43]. Intracellular stress signals, such as oxidative stress, hypoxia, or DNA damage induce BAX and BAK to release mitochondrial proteins, cytochrome c (a well-known activator of caspases [7,31]), and DIABLO into cytoplasm [44,45].
In the recent years, we and others have demonstrated that miRNAs have an instrumental role in apoptosis and in the pathogenesis of myocardial disorders [1,46,47,48,49,50,51,52] (Figure 1).
miR-133a is one of the fundamental miRNAs able to enhance the survival of cardiomyocytes in anoxia and hypoxia conditions. Indeed, miR-133a inhibits apoptosis via repressing Transgelin 2 (TAGLN2), chaperonins heat shock protein 60 and 70 (HSP60, HSP70), apoptotic protease activating factor-1 (Apaf-1), caspase-3/8/9, and by indirectly enhancing Bcl-2 expression [53,54,55,56]. Instead, miR-1 is downregulated under hypoxia, and its overexpression elevates cell apoptosis by reducing Bcl-2 [57].
The upregulation of miR-122 has been reported in rat cardiomyocytes after hypoxia-reoxygenation treatment; miR-122 overexpression promotes cell apoptosis via targeting GATA-4 [58]. Liu et al. found in H9c2 cardiomyoblasts that miR-208a triggers apoptosis through silencing activated protein C (APC) in hypoxic conditions; APC reduces apoptosis in hypoxia and knockdown of APC attenuates the inhibitory effects of miR-208a [59]. A recent study revealed that the upregulation of miR-137-3p can aggravate cardiomyocyte apoptosis induced by ischemia/reperfusion through means of the downregulation of the Kruppel-like factor 15 (KLF15). [60]. In vitro, a significant downregulation of miR-7a-5p was detected in H9c2 cardiomyoblasts undergoing hypoxia-reoxygenation; this finding is noteworthy, inasmuch as the overexpression of miR-7a-5p inhibits the expression of cleaved caspase-3 and Bax and promotes the expression of Bcl-2 by targeting voltage-dependent anion channel 1 (VDAC1) [61].
Wu et al. demonstrated that miR-613 attenuates cell apoptosis by targeting Programmed cell death 10 (PDCD10) in cardiomyocytes undergoing ischemia/reperfusion [62]. Hypoxia treatment also augments miR-9 expression levels, and miR-9 enhances cell apoptosis via repressing CDK8; in fact, knockdown of CDK8 reverses the inhibitory effects of miR-9 downregulation and increases cell apoptosis [63].
Hypoxia-reoxygenation was shown to reduce miR-24 expression in rat cardiomyocytes, whereas miR-24 mimics increase Bcl-2 protein levels and decrease apoptosis [64]; equally important, Mitogen-Activated Protein Kinase 14 (MAPK14) is a target gene of miR-24 and its expression is negatively regulated by this miR [64]. Notably, miR-135a overexpression is known to decrease cell apoptosis, lactate dehydrogenase levels, Troponin I, and inflammation following isoproterenol treatment [65]; luciferase assay analyses validated Toll-like receptor 4 (TLR4) as the specific target gene of miR-135a [65]. RT-qPCR and immunoblot analyses revealed that oxygen-glucose deprivation/reperfusion (OGD/R) injury significantly enhances miR-210 in primary cardiomyocytes. Decreased caspase-3 activity and cell apoptosis was detected in cells transfected with a miR-210 mimic; furthermore, the transcription factor E2F3, known to trigger cell apoptosis [66], is one of target genes of miR-210 [67].
Emerging evidence indicates a significant downregulation of miR-26a-5p expression in mice undergoing ischemia/reperfusion injury, as well as in cardiomyocytes undergoing hypoxia-reoxygenation. Overexpression of miR-26a-5p significantly inhibits cardiomyocyte apoptosis and improves cardiac function by repressing Phosphatase and tensin homolog (PTEN), thereby activating the PI3K/AKT signaling pathway; thus, miR-26a-5p protects cardiac function via regulating PTEN/PI3K/AKT upon ischemia/reperfusion injury [68]. Wang et al. demonstrated that miR-369 overexpression reduces cell apoptosis, inflammation, and is accompanied by decreased caspase-3 activity, secretion of interleukin (IL)-6, IL-1β, and TNF-α by suppressing Transient Receptor Potential Cation Channel Subfamily V Member 3 (TRPV3) [69]. When overexpressed in rat cardiomyocytes under hypoxia-reoxygenation conditions, miR-129-5p decreases cell death by targeting HMGB1 [70]. miR-147 was shown to be downregulated after hypoxia in rat cardiomyocytes and, in vivo, in a rat model of myocardial infarction; overexpression of this miRNA preserves cardiac function by silencing homeodomain interacting protein kinase 2 (HIPK2) [71]. miR-184 depletion in vitro was found to decrease cleaved caspase-3 and Bax and attenuate cell death in cardiomyocytes by targeting F-box protein 28 (FBXO28) under hypoxic conditions [72]. Liu et al. observed that the overexpression of miR-223 reduces cell apoptosis by inhibition of poly (ADP-ribose) polymerase 1 (PARP-1) in rats with myocardial infarction and in hypoxia-treated neonatal rat cardiomyocytes (NRCMs); PARP-1 is a downstream target of miR-223 and these researchers found that silencing PARP-1 can protect cardiomyocytes from hypoxia [73].
There is an interaction between the lncRNA taurine up-regulated gene 1 (TUG1) and miR-142-3p [74]. High mobility group box 1 protein (HMGB1) and Ras-related C3 botulinum toxin substrate 1 (Rac1) are key regulators of apoptosis. Overexpression of miR-142-3p can preserve cardiomyocytes under hypoxia from apoptosis by inhibiting HMGB1 and Rac1 [75].
Dual-luciferase reporter assay revealed that the secreted protein acidic and rich in cysteine (SPARC) is a direct target of miR-29b-3p [76]. Hypoxia decreases miR-29b-3p expression in H9c2 cardiomyoblasts and increases cell apoptosis. Overexpression of miR-29b-3p can protect H9c2 cells from apoptosis by reducing the TGF-β1/SMAD pathway and SPARC [76].

4. miRNAs and Cardiomyocyte Autophagy

Autophagy (from the Ancient Greek αὐτόφαγος autóphagos, meaning “self-devouring”) is a highly conserved process in which cells eliminate cytoplasmic components, such as damaged proteins, substrates, and organelles in a lysosomal-dependent-way [77,78,79,80]. Autophagy is a pro-survival mechanism, activated through two major pathways including mTOR (mammalian or mechanistic target of rapamycin) and Bcl2 [81,82], that plays important roles in maintaining homeostasis [83]. Hypoxia, nutrient starvation, toxic agents, and stress can induce autophagy [84,85], a process that is known to have beneficial effects on myocardial cells, especially during the reperfusion stage [86,87,88,89].
There are numerus miRNAs that protect myocardial injury by regulating autophagy (Table 1). For instance, miR-34a attenuates autophagy by decreasing the expression of Lc3-II, p62, and TNF-α in neonatal rat cardiomyocytes in hypoxia-reoxygenation conditions [90].
In anoxia/reoxygenation (A/R)-treated rat cardiomyocytes and infarcted murine hearts, inhibition of miR-429 by antagomiR-429, increases the expression of MO25, LKB1, pAMPKα, ATG13, p62, and LC3B-I/II. Overexpression of miR-429 induces cell apoptosis and reduces autophagy. Antagonism of miR-429 improves hypoxia injury by enrichment of MO25/LKB1/AMPK mediated autophagy [91].
Autophagy-related 7 (ATG7) was identified as a target gene of miR-542-5p in H9c2 cardiomyoblasts [92], whereas the overexpression of miR-208a-3p indirectly upregulates autophagy related 5 (ATG5) [93] by downregulating Programmed Cell Death 4 (PDCD4) [94]. In a rabbit model of myocardial infarction and in H9c2 rat cardiomyoblasts, miR-145 was shown to have a cardioprotective effect through the induction of cardiomyocyte autophagy by targeting fibroblast growth factor receptor substrate 2 (FRS2). Downregulation of miR-142-5p and miR-126 stimulate autophagy by increasing the levels of beclin-1 [95,96], a major player in cardiac autophagy [97]. Overexpression of miR-204 targets beclin-1 and blocks the transformation of LC3-I to LC3-II; miR-204 attenuates apoptosis via targeting SIRT1 in H9c2 cells under hypoxia-reoxygenation conditions [98,99].
Heat Shock Protein Family A member 5 (HSPA5) and MAPK-mTOR signaling are downstream of miR-199a: the downregulation of miR-199a suppresses autophagy by inhibiting HSPA5 and MAPK-mTOR signaling in rat cardiomyocytes under starvation [100]. The miR-212/miR-132 family directly targets the pro-autophagic FoxO3 transcription factor and overexpression of these miRNAs leads to an impaired autophagic response [101]; similarly, Lv et al. observed upregulation of miR-302a-3p in mice undergoing ischemia/reperfusion, and miR-302a-3p upregulation inhibits FOXO3 [102]. Intriguingly, miR-19a decreases cell apoptosis and necrosis via repression of Bim, a proapoptotic protein, and switches on autophagy in rat cardiomyocytes under hypoxia [103]; equally important, miR-30e-3p promotes cardiomyocyte autophagy and inhibits apoptosis by indirectly regulating the expression of Egr-1 (Early growth response-1), a zinc finger transcriptional protein that has been associated with cardiovascular disorders [104], in an ischemic/hypoxic environment [105]. Most recently, the inhibition of miR-17-5p was shown to inhibit myocardial autophagy through targeting STAT3 [106].
Long non-coding RNAs (lncRNAs) have been extensively investigated in cardiomyocyte autophagy: the lncRNA DCM-related factor (DCRF) regulates cardiomyocyte autophagy by targeting miR-551b-5p [107], the lncRNA autophagy promoting factor (APF) regulates autophagy and myocardial infarction by targeting miR-188-3p [108], and the lncRNA 2810403D21Rik/Mirf (myocardial infarction-regulatory factor) acts as a competitive endogenous RNA (ceRNA) of miR-26a: downregulation of 2810403D21Rik/Mirf results in upregulation of miR-26a to promote autophagy by targeting ubiquitin specific peptidase 15 (Usp15) [109].
The main miRs involved in the regulation of cardiomyocyte apoptosis, necrosis, and autophagy are reported in Table 1.
Table
Table 1. Main miRNAs linked to regulation of apoptosis, necrosis, and autophagy in cardiovascular disorders.
Table 1. Main miRNAs linked to regulation of apoptosis, necrosis, and autophagy in cardiovascular disorders.
MechanismsmiRNATarget Gene(s)References
ApoptosismiR-1Bcl2[57]
miR-7a-5pVDAC1[61]
miR-9CDK8[63]
miR-24Mapk14[64]
miR-26a-5pPTEN/PI3K/AKT[68]
miR-29b-3p SPARC/TGF-β1/SMAD[76]
miR-122 GATA-4[58]
miR-129-5pHMGB1[70]
miR-133aTAGLN2, HSP60, HSP70, Apaf1, Caspase3,8,9[53,54,55,56]
miR-135aTLR4[65]
miR-137-3pKLF15 [60]
miR-142-3pHMGB1, Rac1[75]
miR-147HIPK2[71]
miR-184FBXO28[72]
miR-208aAPC[59]
miR-210E2F3[67]
miR-223PARP-1[73]
miR-369TRPV3[69]
miR-613PDCD10[62]
NecrosismiR-30bCypD[18]
miR-103/107FADD[15]
miR-155RIP1[23]
miR-325-3pPIPK3[22]
miR-874Caspase-8[20]
miR-873P53[16]
miR-2861ANT1[26]
AutophagymiR-17-5pSTAT3[106]
miR-19aBim[103]
miR-26aUsp15[109]
miR-30e-3pEgr-1[104]
miR-34aLc3-II, p62, TNF-α[90]
miR-126Beclin-1[96]
miR-132FoxO3[101]
miR-142-5pBeclin-1[95]
miR-145FRS2[110]
miR-199aHSPA5/MAPK-mTOR[100]
miR-204SIRT1[98,99]
miR-208a-3pPDCD4[94]
miR-212FoxO3[101]
miR-302a-3pFoxO3[102]
miR-429MO25/LKB1/AMPK[91]
miR-542-5pATG7[92]
miR-551b-5pPCDH17[107]

5. Clinical Studies: miRNAs as Biomarkers and Potential Therapies

Cardiac troponin I (cTnI), creatine kinase isoenzyme (CKMB), and brain natriuretic peptide (BNP) are extensively used for diagnosis of ischemic cardiovascular disorders [111]. Recently, miRNAs have been identified as reliable biomarkers for the early detection of cardiovascular diseases. For instance, several studies have shown that the expression of miR-499, miR-636, miR-380, miR-133a, miR-17, miR-21, miR-29b, miR-192, miR-194, miR-499, miR-1915, miR-34a, miR-423, miR-328, miR-134, miR-1254, miR-1, miR-181c, miR-208b, miR-566, miR-7-1, miR-92a, miR-455-3p, miR-126, miR-423-5p, miR-636, miR-486, and miR-1291 is increased in patients with acute myocardial infarction [112,113,114,115,116,117,118,119,120,121]. Equally important, plasma levels of miR-18a, miR-26b, miR-106a, miR-30e, miR-27a, and miR-199a have been found to be downregulated and miR-30d, miR-126, miR-1254, miR-37, miR-30c, miR-223-3p, miR-301a-3p, miR-210, miR-145-5p, miR-29a-3p, miR-1306-5p, miR-26b-5p, miR-199a-3p, miR-92a-3p, miR-146a, and miR-221 are upregulated in patients with heart failure (Table 2) [122,123,124,125,126,127,128,129,130,131,132,133].
The US Food and Drug Administration has already approved various RNA-based drugs targeting cardiovascular diseases and the pharmaceutical development of miRNA therapeutics is also in progress. In order to advance towards actual clinical application, proof of concept and safety evaluations must be carried out in large animal models, such as pigs and nonhuman primates. To study myocardial infarction, pigs are ideal for mimicking human heart disease as the porcine heart resembles the human heart in terms of weight, heart rate, and blood pressure [134].
Ex vivo models, including engineered heart tissue (EHTs) and living myocardial slices derived from human cells or tissues, are used as a bridge between in vitro and in vivo studies. Differentiated cardiomyocytes from human induced pluripotent stem cells (hiPSC) do not fully recapitulate the complex intercellular interactions observed in the whole human heart. Instead, several studies have shown that EHTs can recapitulate chronic heart disease phenotypes and miRNA-based drug development [135,136,137].
In an in vivo study carried out in mice, miR-92a was found to be overexpressed following cardiac ischemic injury; strikingly, administering antimiR-92a encapsulated in bioabsorbable and biocompatible microspheres via intracoronary injections in a swine model of myocardial infarction substantially improved angiogenesis [138]. A miR-92a inhibitor (Drug: MRG-110) intending to promote angiogenesis is currently under investigation in phase I clinical trials (Clinical Trial Identifiers: NCT03603431 and NCT03494712).
Another miRNA that is undergoing a Phase Ib clinical trial is miR-132 (Clinical Trial Identifiers: NCT04045405). Foinquinos et al. reported strong evidence for therapeutic efficacy of a locked nucleic acid based antisense inhibitor of miR-132 (antimiR-132) in a swine model of heart failure [101,139]. A miR-132 inhibitor (known as CDR132L) significantly preserves cardiac function and reverses cardiac remodeling in heart failure patients [140].

6. Conclusions

The overview on miRs modulating cardiomyocyte death presented here underlies the active research in this area and embodies a useful guide for the investigators in this field. Considering that targeting miRs and other non-coding RNAs represents a specific strategy to counteract cardiomyocyte death, we anticipate substantial research in this direction in the next years.

Author Contributions

Conceptualization, G.S.; writing—original draft preparation, U.K. and F.V.; writing—review and editing, P.M., S.S.J. and G.S.; supervision, G.S. All authors have read and agreed to the published version of the manuscript.

Funding

The Santulli’s Lab is supported in part by the National Institutes of Health (NIH: R01-HL159062, R01-DK123259, R01-HL146691, R01-DK033823, R56-AG066431, T32-HL144456, and R00-DK107895, to G.S.), by the Irma T. Hirschl and Monique Weill-Caulier Trusts (to G.S.), and by the Diabetes Action Research and Education Foundation (to G.S.); F.V. and S.S.J. hold postdoctoral fellowships from the American Heart Association (AHA-22POST915561 and AHA-21POST836407, respectively).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Santulli, G. MicroRNA: From Molecular Biology to Clinical Practice; Santulli, G., Ed.; Springer Nature: New York, NY, USA, 2016. [Google Scholar]
  2. Yoshida, T.; Asano, Y.; Ui-Tei, K. Modulation of MicroRNA Processing by Dicer via Its Associated dsRNA Binding Proteins. Noncoding RNA 2021, 7, 57. [Google Scholar] [CrossRef] [PubMed]
  3. O’Brien, J.; Hayder, H.; Zayed, Y.; Peng, C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Front. Endocrinol. 2018, 9, 402. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Varzideh, F.; Kansakar, U.; Donkor, K.; Wilson, S.; Jankauskas, S.; Mone, P.; Wang, X.; Lombardi, A.; Santulli, G. Cardiac remodeling after myocardial infarction: Functional contribution of microRNAs to inflammation and fibrosis. Front. Cardiovasc. Med. 2022; in press. [Google Scholar]
  5. Del Re, D.P.; Amgalan, D.; Linkermann, A.; Liu, Q.; Kitsis, R.N. Fundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease. Physiol. Rev. 2019, 99, 1765–1817. [Google Scholar] [CrossRef] [PubMed]
  6. Chiong, M.; Wang, Z.V.; Pedrozo, Z.; Cao, D.J.; Troncoso, R.; Ibacache, M.; Criollo, A.; Nemchenko, A.; Hill, J.A.; Lavandero, S. Cardiomyocyte death: Mechanisms and translational implications. Cell Death Dis. 2011, 2, e244. [Google Scholar] [CrossRef] [PubMed]
  7. Konstantinidis, K.; Whelan, R.S.; Kitsis, R.N. Mechanisms of cell death in heart disease. Arterioscler. Thromb. Vasc. Biol. 2012, 32, 1552–1562. [Google Scholar] [CrossRef] [Green Version]
  8. Kalogeris, T.; Baines, C.P.; Krenz, M.; Korthuis, R.J. Cell biology of ischemia/reperfusion injury. Int. Rev. Cell Mol. Biol. 2012, 298, 229–317. [Google Scholar] [CrossRef]
  9. Li, L.; Tong, A.; Zhang, Q.; Wei, Y.; Wei, X. The molecular mechanisms of MLKL-dependent and MLKL-independent necrosis. J. Mol. Cell Biol. 2021, 13, 3–14. [Google Scholar] [CrossRef] [PubMed]
  10. Kist, M.; Vucic, D. Cell death pathways: Intricate connections and disease implications. EMBO J. 2021, 40, e106700. [Google Scholar] [CrossRef]
  11. Zhu, H.; Sun, A. Programmed necrosis in heart disease: Molecular mechanisms and clinical implications. J. Mol. Cell. Cardiol. 2018, 116, 125–134. [Google Scholar] [CrossRef]
  12. Zhang, J.; Liu, D.; Zhang, M.; Zhang, Y. Programmed necrosis in cardiomyocytes: Mitochondria, death receptors and beyond. Br. J. Pharmacol. 2019, 176, 4319–4339. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Wu, W.; Liu, P.; Li, J. Necroptosis: An emerging form of programmed cell death. Crit. Rev. Oncol. Hematol. 2012, 82, 249–258. [Google Scholar] [CrossRef] [PubMed]
  14. Dong, Y.; Liu, C.; Zhao, Y.; Ponnusamy, M.; Li, P.; Wang, K. Role of noncoding RNAs in regulation of cardiac cell death and cardiovascular diseases. Cell. Mol. Life Sci. 2018, 75, 291–300. [Google Scholar] [CrossRef] [PubMed]
  15. Wang, J.X.; Zhang, X.J.; Li, Q.; Wang, K.; Wang, Y.; Jiao, J.Q.; Feng, C.; Teng, S.; Zhou, L.Y.; Gong, Y.; et al. MicroRNA-103/107 Regulate Programmed Necrosis and Myocardial Ischemia/Reperfusion Injury Through Targeting FADD. Circ. Res. 2015, 117, 352–363. [Google Scholar] [CrossRef] [Green Version]
  16. Wang, K.; Liu, F.; Liu, C.Y.; An, T.; Zhang, J.; Zhou, L.Y.; Wang, M.; Dong, Y.H.; Li, N.; Gao, J.N.; et al. The long noncoding RNA NRF regulates programmed necrosis and myocardial injury during ischemia and reperfusion by targeting miR-873. Cell Death Differ. 2016, 23, 1394–1405. [Google Scholar] [CrossRef] [Green Version]
  17. Yamada, K.; Yoshida, K. Mechanical insights into the regulation of programmed cell death by p53 via mitochondria. Biochim. Biophys. Acta Mol. Cell Res. 2019, 1866, 839–848. [Google Scholar] [CrossRef] [PubMed]
  18. Wang, K.; An, T.; Zhou, L.Y.; Liu, C.Y.; Zhang, X.J.; Feng, C.; Li, P.F. E2F1-regulated miR-30b suppresses Cyclophilin D and protects heart from ischemia/reperfusion injury and necrotic cell death. Cell Death Differ. 2015, 22, 743–754. [Google Scholar] [CrossRef] [Green Version]
  19. Feng, S.; Yang, Y.; Mei, Y.; Ma, L.; Zhu, D.E.; Hoti, N.; Castanares, M.; Wu, M. Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. Cell Signal. 2007, 19, 2056–2067. [Google Scholar] [CrossRef]
  20. Wang, K.; Liu, F.; Zhou, L.Y.; Ding, S.L.; Long, B.; Liu, C.Y.; Sun, T.; Fan, Y.Y.; Sun, L.; Li, P.F. miR-874 regulates myocardial necrosis by targeting caspase-8. Cell Death Dis. 2013, 4, e709. [Google Scholar] [CrossRef] [Green Version]
  21. Xin, Z.; Ma, Z.; Jiang, S.; Wang, D.; Fan, C.; Di, S.; Hu, W.; Li, T.; She, J.; Yang, Y. FOXOs in the impaired heart: New therapeutic targets for cardiac diseases. Biochim. Biophys. Acta Mol. Basis Dis. 2017, 1863, 486–498. [Google Scholar] [CrossRef]
  22. Zhang, D.Y.; Wang, B.J.; Ma, M.; Yu, K.; Zhang, Q.; Zhang, X.W. MicroRNA-325-3p protects the heart after myocardial infarction by inhibiting RIPK3 and programmed necrosis in mice. BMC Mol. Biol. 2019, 20, 17. [Google Scholar] [CrossRef]
  23. Liu, J.; van Mil, A.; Vrijsen, K.; Zhao, J.; Gao, L.; Metz, C.H.; Goumans, M.J.; Doevendans, P.A.; Sluijter, J.P. MicroRNA-155 prevents necrotic cell death in human cardiomyocyte progenitor cells via targeting RIP1. J. Cell. Mol. Med. 2011, 15, 1474–1482. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Jankauskas, S.S.; Gambardella, J.; Sardu, C.; Lombardi, A.; Santulli, G. Functional Role of miR-155 in the Pathogenesis of Diabetes Mellitus and Its Complications. Noncoding RNA 2021, 7, 39. [Google Scholar] [CrossRef] [PubMed]
  25. Pan, S.; Wang, N.; Bisetto, S.; Yi, B.; Sheu, S.S. Downregulation of adenine nucleotide translocator 1 exacerbates tumor necrosis factor-alpha-mediated cardiac inflammatory responses. Am. J. Physiol. Heart Circ. Physiol. 2015, 308, H39–H48. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Wang, K.; Long, B.; Li, N.; Li, L.; Liu, C.Y.; Dong, Y.H.; Gao, J.N.; Zhou, L.Y.; Wang, C.Q.; Li, P.F. MicroRNA-2861 regulates programmed necrosis in cardiomyocyte by impairing adenine nucleotide translocase 1 expression. Free Radic. Biol. Med. 2016, 91, 58–67. [Google Scholar] [CrossRef] [PubMed]
  27. Gerschenson, L.E.; Geske, F.J. Virchow and apoptosis. Am. J. Pathol. 2001, 158, 1543. [Google Scholar] [CrossRef]
  28. Kerr, J.F.; Wyllie, A.H.; Currie, A.R. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 1972, 26, 239–257. [Google Scholar] [CrossRef] [Green Version]
  29. Kim, N.H.; Kang, P.M. Apoptosis in cardiovascular diseases: Mechanism and clinical implications. Korean Circ. J. 2010, 40, 299–305. [Google Scholar] [CrossRef] [Green Version]
  30. Lee, Y.; Gustafsson, A.B. Role of apoptosis in cardiovascular disease. Apoptosis 2009, 14, 536–548. [Google Scholar] [CrossRef]
  31. Teringova, E.; Tousek, P. Apoptosis in ischemic heart disease. J. Transl. Med. 2017, 15, 87. [Google Scholar] [CrossRef] [Green Version]
  32. Haunstetter, A.; Izumo, S. Apoptosis: Basic mechanisms and implications for cardiovascular disease. Circ. Res. 1998, 82, 1111–1129. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Orogo, A.M.; Gustafsson, A.B. Cell death in the myocardium: My heart won’t go on. IUBMB Life 2013, 65, 651–656. [Google Scholar] [CrossRef] [PubMed]
  34. Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol. 2007, 35, 495–516. [Google Scholar] [CrossRef] [PubMed]
  35. Green, D.R.; Llambi, F. Cell Death Signaling. Cold Spring Harb. Perspect. Biol. 2015, 7, a006080. [Google Scholar] [CrossRef] [PubMed]
  36. Guicciardi, M.E.; Gores, G.J. Life and death by death receptors. FASEB J. 2009, 23, 1625–1637. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Crow, M.T.; Mani, K.; Nam, Y.J.; Kitsis, R.N. The mitochondrial death pathway and cardiac myocyte apoptosis. Circ. Res. 2004, 95, 957–970. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Hardwick, J.M.; Soane, L. Multiple functions of BCL-2 family proteins. Cold Spring Harb. Perspect. Biol. 2013, 5. [Google Scholar] [CrossRef] [Green Version]
  39. Leibowitz, B.; Yu, J. Mitochondrial signaling in cell death via the Bcl-2 family. Cancer Biol. Ther. 2010, 9, 417–422. [Google Scholar] [CrossRef] [Green Version]
  40. Tsujimoto, Y. Role of Bcl-2 family proteins in apoptosis: Apoptosomes or mitochondria? Genes Cells 1998, 3, 697–707. [Google Scholar] [CrossRef]
  41. Galluzzi, L.; Vitale, I.; Aaronson, S.A.; Abrams, J.M.; Adam, D.; Agostinis, P.; Alnemri, E.S.; Altucci, L.; Amelio, I.; Andrews, D.W.; et al. Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018, 25, 486–541. [Google Scholar] [CrossRef]
  42. Amgalan, D.; Garner, T.P.; Pekson, R.; Jia, X.F.; Yanamandala, M.; Paulino, V.; Liang, F.G.; Corbalan, J.J.; Lee, J.; Chen, Y.; et al. A small-molecule allosteric inhibitor of BAX protects against doxorubicin-induced cardiomyopathy. Nat. Cancer 2020, 1, 315–328. [Google Scholar] [CrossRef] [PubMed]
  43. Karch, J.; Kwong, J.Q.; Burr, A.R.; Sargent, M.A.; Elrod, J.W.; Peixoto, P.M.; Martinez-Caballero, S.; Osinska, H.; Cheng, E.H.; Robbins, J.; et al. Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice. eLife 2013, 2, e00772. [Google Scholar] [CrossRef] [PubMed]
  44. Redza-Dutordoir, M.; Averill-Bates, D.A. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim. Biophys. Acta 2016, 1863, 2977–2992. [Google Scholar] [CrossRef] [PubMed]
  45. Kilbride, S.M.; Prehn, J.H. Central roles of apoptotic proteins in mitochondrial function. Oncogene 2013, 32, 2703–2711. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Xiong, W.; Qu, Y.; Chen, H.; Qian, J. Insight into long noncoding RNA-miRNA-mRNA axes in myocardial ischemia-reperfusion injury: The implications for mechanism and therapy. Epigenomics 2019, 11, 1733–1748. [Google Scholar] [CrossRef]
  47. Santulli, G. microRNAs Distinctively Regulate Vascular Smooth Muscle and Endothelial Cells: Functional Implications in Angiogenesis, Atherosclerosis, and In-Stent Restenosis. Adv. Exp. Med. Biol. 2015, 887, 53–77. [Google Scholar] [CrossRef]
  48. Wronska, A.; Kurkowska-Jastrzebska, I.; Santulli, G. Application of microRNAs in diagnosis and treatment of cardiovascular disease. Acta Physiol. 2015, 213, 60–83. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Balamurali, D.; Stoll, M. Non-Coding RNA Databases in Cardiovascular Research. Noncoding RNA 2020, 6, 35. [Google Scholar] [CrossRef]
  50. Gandhi, S.; Ruehle, F.; Stoll, M. Evolutionary Patterns of Non-Coding RNA in Cardiovascular Biology. Noncoding RNA 2019, 5, 15. [Google Scholar] [CrossRef] [Green Version]
  51. Xiao, Y.; Zhao, J.; Tuazon, J.P.; Borlongan, C.V.; Yu, G. MicroRNA-133a and Myocardial Infarction. Cell Transplant. 2019, 28, 831–838. [Google Scholar] [CrossRef] [Green Version]
  52. Chistiakov, D.A.; Orekhov, A.N.; Bobryshev, Y.V. Cardiac-specific miRNA in cardiogenesis, heart function, and cardiac pathology (with focus on myocardial infarction). J. Mol. Cell. Cardiol. 2016, 94, 107–121. [Google Scholar] [CrossRef]
  53. Li, A.Y.; Yang, Q.; Yang, K. miR-133a mediates the hypoxia-induced apoptosis by inhibiting TAGLN2 expression in cardiac myocytes. Mol. Cell. Biochem. 2015, 400, 173–181. [Google Scholar] [CrossRef] [PubMed]
  54. He, B.; Xiao, J.; Ren, A.J.; Zhang, Y.F.; Zhang, H.; Chen, M.; Xie, B.; Gao, X.G.; Wang, Y.W. Role of miR-1 and miR-133a in myocardial ischemic postconditioning. J. Biomed. Sci. 2011, 18, 22. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Xu, C.; Lu, Y.; Pan, Z.; Chu, W.; Luo, X.; Lin, H.; Xiao, J.; Shan, H.; Wang, Z.; Yang, B. The muscle-specific microRNAs miR-1 and miR-133 produce opposing effects on apoptosis by targeting HSP60, HSP70 and caspase-9 in cardiomyocytes. J. Cell Sci. 2007, 120, 3045–3052. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Dakhlallah, D.; Zhang, J.; Yu, L.; Marsh, C.B.; Angelos, M.G.; Khan, M. MicroRNA-133a engineered mesenchymal stem cells augment cardiac function and cell survival in the infarct heart. J. Cardiovasc. Pharmacol. 2015, 65, 241–251. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Tang, Y.; Zheng, J.; Sun, Y.; Wu, Z.; Liu, Z.; Huang, G. MicroRNA-1 regulates cardiomyocyte apoptosis by targeting Bcl-2. Int. Heart J. 2009, 50, 377–387. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Liang, W.; Guo, J.; Li, J.; Bai, C.; Dong, Y. Downregulation of miR-122 attenuates hypoxia/reoxygenation (H/R)-induced myocardial cell apoptosis by upregulating GATA-4. Biochem. Biophys. Res. Commun. 2016, 478, 1416–1422. [Google Scholar] [CrossRef]
  59. Liu, F.; Zhang, H.; Zhang, Z.; Lu, Y.; Lu, X. MiR-208a aggravates H2O2-induced cardiomyocyte injury by targeting APC. Eur. J. Pharmacol. 2019, 864, 172668. [Google Scholar] [CrossRef] [PubMed]
  60. Zhao, T.; Qiu, Z.; Gao, Y. MiR-137-3p exacerbates the ischemia-reperfusion injured cardiomyocyte apoptosis by targeting KLF15. Naunyn Schmiedebergs Arch. Pharmacol. 2020, 393, 1013–1024. [Google Scholar] [CrossRef]
  61. Lu, H.; Zhang, J.; Xuan, F. MiR-7a-5p Attenuates Hypoxia/Reoxygenation-Induced Cardiomyocyte Apoptosis by Targeting VDAC1. Cardiovasc. Toxicol. 2021, 22, 108–117. [Google Scholar] [CrossRef]
  62. Wu, Z.; Qi, Y.; Guo, Z.; Li, P.; Zhou, D. miR-613 suppresses ischemia-reperfusion-induced cardiomyocyte apoptosis by targeting the programmed cell death 10 gene. BioSci. Trends 2016, 10, 251–257. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Dou, P.; Tan, G.; Fan, Z.; Xiao, J.; Shi, C.; Lin, Z. MicroRNA-9 facilitates hypoxia-induced injury and apoptosis in H9c2 cells via targeting CDK8. J. BioSci. 2021, 46, 16. [Google Scholar] [CrossRef] [PubMed]
  64. Qin, S.Q.; Zhang, Z.S.; Wang, X.Y.; Shi, J.Z.; Yang, X.B. MiR-24 Protects Cardiomyocytes Against Hypoxia/Reoxygenation-Induced Injury Through Regulating Mitogen-Activated Protein Kinase 14. Int. Heart J. 2020, 61, 806–814. [Google Scholar] [CrossRef] [PubMed]
  65. Feng, H.; Xie, B.; Zhang, Z.; Yan, J.; Cheng, M.; Zhou, Y. MiR-135a Protects against Myocardial Injury by Targeting TLR4. Chem. Pharm. Bull. 2021, 69, 529–536. [Google Scholar] [CrossRef] [PubMed]
  66. Martinez, L.A.; Goluszko, E.; Chen, H.Z.; Leone, G.; Post, S.; Lozano, G.; Chen, Z.; Chauchereau, A. E2F3 is a mediator of DNA damage-induced apoptosis. Mol. Cell Biol. 2010, 30, 524–536. [Google Scholar] [CrossRef] [Green Version]
  67. Bian, W.S.; Shi, P.X.; Mi, X.F.; Sun, Y.Y.; Yang, D.D.; Gao, B.F.; Wu, S.X.; Fan, G.C. MiR-210 protects cardiomyocytes from OGD/R injury by inhibiting E2F3. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 743–749. [Google Scholar] [CrossRef]
  68. Xing, X.; Guo, S.; Zhang, G.; Liu, Y.; Bi, S.; Wang, X.; Lu, Q. miR-26a-5p protects against myocardial ischemia/reperfusion injury by regulating the PTEN/PI3K/AKT signaling pathway. Braz. J. Med. Biol. Res. 2020, 53, e9106. [Google Scholar] [CrossRef] [Green Version]
  69. Wang, J.; Chen, X.; Huang, W. MicroRNA-369 attenuates hypoxia-induced cardiomyocyte apoptosis and inflammation via targeting TRPV3. Braz. J. Med. Biol. Res. 2021, 54, e10550. [Google Scholar] [CrossRef]
  70. Chen, Z.X.; He, D.; Mo, Q.W.; Xie, L.P.; Liang, J.R.; Liu, L.; Fu, W.J. MiR-129-5p protects against myocardial ischemia-reperfusion injury via targeting HMGB1. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 4440–4450. [Google Scholar] [CrossRef]
  71. Wu, C.G.; Huang, C. MicroRNA-147 inhibits myocardial inflammation and apoptosis following myocardial infarction via targeting HIPK2. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 6279–6287. [Google Scholar] [CrossRef]
  72. Zou, J.F.; Wu, X.N.; Shi, R.H.; Sun, Y.Q.; Qin, F.J.; Yang, Y.M. Inhibition of microRNA-184 reduces H2O2-mediated cardiomyocyte injury via targeting FBXO28. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 11251–11258. [Google Scholar] [CrossRef] [PubMed]
  73. Liu, X.; Deng, Y.; Xu, Y.; Jin, W.; Li, H. MicroRNA-223 protects neonatal rat cardiomyocytes and H9c2 cells from hypoxia-induced apoptosis and excessive autophagy via the Akt/mTOR pathway by targeting PARP-1. J. Mol. Cell. Cardiol. 2018, 118, 133–146. [Google Scholar] [CrossRef] [PubMed]
  74. He, C.; Liu, Z.; Jin, L.; Zhang, F.; Peng, X.; Xiao, Y.; Wang, X.; Lyu, Q.; Cai, X. lncRNA TUG1-Mediated Mir-142-3p Downregulation Contributes to Metastasis and the Epithelial-to-Mesenchymal Transition of Hepatocellular Carcinoma by Targeting ZEB1. Cell. Physiol. Biochem. 2018, 48, 1928–1941. [Google Scholar] [CrossRef] [PubMed]
  75. Su, Q.; Liu, Y.; Lv, X.W.; Ye, Z.L.; Sun, Y.H.; Kong, B.H.; Qin, Z.B. Inhibition of lncRNA TUG1 upregulates miR-142-3p to ameliorate myocardial injury during ischemia and reperfusion via targeting HMGB1- and Rac1-induced autophagy. J. Mol. Cell. Cardiol. 2019, 133, 12–25. [Google Scholar] [CrossRef] [PubMed]
  76. Zhou, S.; Lei, D.; Bu, F.; Han, H.; Zhao, S.; Wang, Y. MicroRNA-29b-3p Targets SPARC Gene to Protect Cardiocytes against Autophagy and Apoptosis in Hypoxic-Induced H9c2 Cells. J. Cardiovasc. Transl. Res. 2019, 12, 358–365. [Google Scholar] [CrossRef] [PubMed]
  77. Chun, Y.; Kim, J. Autophagy: An Essential Degradation Program for Cellular Homeostasis and Life. Cells 2018, 7, 278. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Glick, D.; Barth, S.; Macleod, K.F. Autophagy: Cellular and molecular mechanisms. J. Pathol. 2010, 221, 3–12. [Google Scholar] [CrossRef] [Green Version]
  79. Levine, B.; Kroemer, G. Autophagy in the pathogenesis of disease. Cell 2008, 132, 27–42. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Galluzzi, L.; Baehrecke, E.H.; Ballabio, A.; Boya, P.; Bravo-San Pedro, J.M.; Cecconi, F.; Choi, A.M.; Chu, C.T.; Codogno, P.; Colombo, M.I.; et al. Molecular definitions of autophagy and related processes. EMBO J. 2017, 36, 1811–1836. [Google Scholar] [CrossRef]
  81. Santulli, G.; Totary-Jain, H. Tailoring mTOR-based therapy: Molecular evidence and clinical challenges. Pharmacogenomics 2013, 14, 1517–1526. [Google Scholar] [CrossRef] [Green Version]
  82. Tungsukruthai, S.; Reamtong, O.; Roytrakul, S.; Sukrong, S.; Vinayanwattikun, C.; Chanvorachote, P. Targeting AKT/mTOR and Bcl-2 for Autophagic and Apoptosis Cell Death in Lung Cancer: Novel Activity of a Polyphenol Compound. Antioxidants 2021, 10, 534. [Google Scholar] [CrossRef] [PubMed]
  83. Klionsky, D.J.; Petroni, G.; Amaravadi, R.K.; Baehrecke, E.H.; Ballabio, A.; Boya, P.; Bravo-San Pedro, J.M.; Cadwell, K.; Cecconi, F.; Choi, A.M.K.; et al. Autophagy in major human diseases. EMBO J. 2021, 40, e108863. [Google Scholar] [CrossRef] [PubMed]
  84. He, L.; Zhang, J.; Zhao, J.; Ma, N.; Kim, S.W.; Qiao, S.; Ma, X. Autophagy: The Last Defense against Cellular Nutritional Stress. Adv. Nutr. 2018, 9, 493–504. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Azad, M.B.; Chen, Y.; Gibson, S.B. Regulation of autophagy by reactive oxygen species (ROS): Implications for cancer progression and treatment. Antioxid. Redox Signal. 2009, 11, 777–790. [Google Scholar] [CrossRef] [PubMed]
  86. Sun, T.; Li, M.Y.; Li, P.F.; Cao, J.M. MicroRNAs in Cardiac Autophagy: Small Molecules and Big Role. Cells 2018, 7, 104. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Sciarretta, S.; Hariharan, N.; Monden, Y.; Zablocki, D.; Sadoshima, J. Is autophagy in response to ischemia and reperfusion protective or detrimental for the heart? Pediatr. Cardiol. 2011, 32, 275–281. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Wu, D.; Zhang, K.; Hu, P. The Role of Autophagy in Acute Myocardial Infarction. Front. Pharmacol. 2019, 10, 551. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Santulli, G. Cardioprotective effects of autophagy: Eat your heart out, heart failure! Sci. Transl. Med. 2018, 10, aau0462. [Google Scholar] [CrossRef]
  90. Shao, H.; Yang, L.; Wang, L.; Tang, B.; Wang, J.; Li, Q. MicroRNA-34a protects myocardial cells against ischemia-reperfusion injury through inhibiting autophagy via regulating TNFalpha expression. Biochem. Cell Biol. 2018, 96, 349–354. [Google Scholar] [CrossRef]
  91. Zhu, Q.; Hu, F. Antagonism of miR-429 ameliorates anoxia/reoxygenation injury in cardiomyocytes by enhancing MO25/LKB1/AMPK mediated autophagy. Life Sci. 2019, 235, 116842. [Google Scholar] [CrossRef]
  92. Wang, F.; Min, X.; Hu, S.Y.; You, D.L.; Jiang, T.T.; Wang, L.; Wu, X. Hypoxia/reoxygenation-induced upregulation of miRNA-542-5p aggravated cardiomyocyte injury by repressing autophagy. Hum. Cell 2021, 34, 349–359. [Google Scholar] [CrossRef] [PubMed]
  93. Song, X.; Zhang, X.; Wang, X.; Zhu, F.; Guo, C.; Wang, Q.; Shi, Y.; Wang, J.; Chen, Y.; Zhang, L. Tumor suppressor gene PDCD4 negatively regulates autophagy by inhibiting the expression of autophagy-related gene ATG5. Autophagy 2013, 9, 743–755. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Wang, L.; Ye, N.; Lian, X.; Peng, F.; Zhang, H.; Gong, H. MiR-208a-3p aggravates autophagy through the PDCD4-ATG5 pathway in Ang II-induced H9c2 cardiomyoblasts. Biomed. Pharmacother 2018, 98, 1–8. [Google Scholar] [CrossRef] [PubMed]
  95. Huang, P.; Lin, Q.; Liu, X. MicroRNA-142-5p inhibits autophagy in cardiomyocytes in a mouse model of hypoxia/reoxygenation. FEBS Open Bio 2020, 12, 333. [Google Scholar] [CrossRef]
  96. Shi, C.C.; Pan, L.Y.; Peng, Z.Y.; Li, J.G. MiR-126 regulated myocardial autophagy on myocardial infarction. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 6971–6979. [Google Scholar] [CrossRef]
  97. Maejima, Y.; Isobe, M.; Sadoshima, J. Regulation of autophagy by Beclin 1 in the heart. J. Mol. Cell. Cardiol. 2016, 95, 19–25. [Google Scholar] [CrossRef] [Green Version]
  98. Qiu, R.; Li, W.; Liu, Y. MicroRNA-204 protects H9C2 cells against hypoxia/reoxygenation-induced injury through regulating SIRT1-mediated autophagy. Biomed. Pharmacother. 2018, 100, 15–19. [Google Scholar] [CrossRef]
  99. Xiao, J.; Zhu, X.; He, B.; Zhang, Y.; Kang, B.; Wang, Z.; Ni, X. MiR-204 regulates cardiomyocyte autophagy induced by ischemia-reperfusion through LC3-II. J. Biomed. Sci. 2011, 18, 35. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. Chen, L.; Wang, F.Y.; Zeng, Z.Y.; Cui, L.; Shen, J.; Song, X.W.; Li, P.; Zhao, X.X.; Qin, Y.W. MicroRNA-199a acts as a potential suppressor of cardiomyocyte autophagy through targeting Hspa5. Oncotarget 2017, 8, 63825–63834. [Google Scholar] [CrossRef] [Green Version]
  101. Ucar, A.; Gupta, S.K.; Fiedler, J.; Erikci, E.; Kardasinski, M.; Batkai, S.; Dangwal, S.; Kumarswamy, R.; Bang, C.; Holzmann, A.; et al. The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy. Nat. Commun. 2012, 3, 1078. [Google Scholar] [CrossRef]
  102. Lv, W.; Jiang, J.; Li, Y.; Fu, L.; Meng, F.; Li, J. MiR-302a-3p aggravates myocardial ischemia-reperfusion injury by suppressing mitophagy via targeting FOXO3. Exp. Mol. Pathol. 2020, 117, 104522. [Google Scholar] [CrossRef] [PubMed]
  103. Gao, Y.H.; Qian, J.Y.; Chen, Z.W.; Fu, M.Q.; Xu, J.F.; Xia, Y.; Ding, X.F.; Yang, X.D.; Cao, Y.Y.; Zou, Y.Z.; et al. Suppression of Bim by microRNA-19a may protect cardiomyocytes against hypoxia-induced cell death via autophagy activation. Toxicol. Lett. 2016, 257, 72–83. [Google Scholar] [CrossRef] [PubMed]
  104. Khachigian, L.M. Early growth response-1 in the pathogenesis of cardiovascular disease. J. Mol. Med. 2016, 94, 747–753. [Google Scholar] [CrossRef] [PubMed]
  105. Su, B.; Wang, X.; Sun, Y.; Long, M.; Zheng, J.; Wu, W.; Li, L. miR-30e-3p Promotes Cardiomyocyte Autophagy and Inhibits Apoptosis via Regulating Egr-1 during Ischemia/Hypoxia. BioMed Res. Int. 2020, 2020, 7231243. [Google Scholar] [CrossRef] [PubMed]
  106. Chen, B.; Yang, Y.; Wu, J.; Song, J.; Lu, J. microRNA-17-5p downregulation inhibits autophagy and myocardial remodelling after myocardial infarction by targeting STAT3. Autoimmunity 2021, 55, 43–51. [Google Scholar] [CrossRef] [PubMed]
  107. Feng, Y.; Xu, W.; Zhang, W.; Wang, W.; Liu, T.; Zhou, X. LncRNA DCRF regulates cardiomyocyte autophagy by targeting miR-551b-5p in diabetic cardiomyopathy. Theranostics 2019, 9, 4558–4566. [Google Scholar] [CrossRef]
  108. Wang, K.; Liu, C.Y.; Zhou, L.Y.; Wang, J.X.; Wang, M.; Zhao, B.; Zhao, W.K.; Xu, S.J.; Fan, L.H.; Zhang, X.J.; et al. APF lncRNA regulates autophagy and myocardial infarction by targeting miR-188-3p. Nat. Commun. 2015, 6, 6779. [Google Scholar] [CrossRef] [Green Version]
  109. Liang, H.; Su, X.; Wu, Q.; Shan, H.; Lv, L.; Yu, T.; Zhao, X.; Sun, J.; Yang, R.; Zhang, L.; et al. LncRNA 2810403D21Rik/Mirf promotes ischemic myocardial injury by regulating autophagy through targeting Mir26a. Autophagy 2020, 16, 1077–1091. [Google Scholar] [CrossRef]
  110. Higashi, K.; Yamada, Y.; Minatoguchi, S.; Baba, S.; Iwasa, M.; Kanamori, H.; Kawasaki, M.; Nishigaki, K.; Takemura, G.; Kumazaki, M.; et al. MicroRNA-145 repairs infarcted myocardium by accelerating cardiomyocyte autophagy. Am. J. Physiol. Heart Circ. Physiol. 2015, 309, H1813–H1826. [Google Scholar] [CrossRef] [Green Version]
  111. Endo, K.; Naito, Y.; Ji, X.; Nakanishi, M.; Noguchi, T.; Goto, Y.; Nonogi, H.; Ma, X.; Weng, H.; Hirokawa, G.; et al. MicroRNA 210 as a biomarker for congestive heart failure. Biol. Pharm. Bull. 2013, 36, 48–54. [Google Scholar] [CrossRef] [Green Version]
  112. Watson, C.J.; Gupta, S.K.; O’Connell, E.; Thum, S.; Glezeva, N.; Fendrich, J.; Gallagher, J.; Ledwidge, M.; Grote-Levi, L.; McDonald, K.; et al. MicroRNA signatures differentiate preserved from reduced ejection fraction heart failure. Eur. J. Heart Fail. 2015, 17, 405–415. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Marfella, R.; Di Filippo, C.; Potenza, N.; Sardu, C.; Rizzo, M.R.; Siniscalchi, M.; Musacchio, E.; Barbieri, M.; Mauro, C.; Mosca, N.; et al. Circulating microRNA changes in heart failure patients treated with cardiac resynchronization therapy: Responders vs. non-responders. Eur. J. Heart Fail. 2013, 15, 1277–1288. [Google Scholar] [CrossRef] [Green Version]
  114. Ovchinnikova, E.S.; Schmitter, D.; Vegter, E.L.; Ter Maaten, J.M.; Valente, M.A.; Liu, L.C.; van der Harst, P.; Pinto, Y.M.; de Boer, R.A.; Meyer, S.; et al. Signature of circulating microRNAs in patients with acute heart failure. Eur. J. Heart Fail. 2016, 18, 414–423. [Google Scholar] [CrossRef]
  115. Sygitowicz, G.; Tomaniak, M.; Blaszczyk, O.; Koltowski, L.; Filipiak, K.J.; Sitkiewicz, D. Circulating microribonucleic acids miR-1, miR-21 and miR-208a in patients with symptomatic heart failure: Preliminary results. Arch. Cardiovasc. Dis. 2015, 108, 634–642. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Gidlof, O.; Smith, J.G.; Miyazu, K.; Gilje, P.; Spencer, A.; Blomquist, S.; Erlinge, D. Circulating cardio-enriched microRNAs are associated with long-term prognosis following myocardial infarction. BMC Cardiovasc. Disord. 2013, 13, 12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Tijsen, A.J.; Creemers, E.E.; Moerland, P.D.; de Windt, L.J.; van der Wal, A.C.; Kok, W.E.; Pinto, Y.M. MiR423-5p as a circulating biomarker for heart failure. Circ. Res. 2010, 106, 1035–1039. [Google Scholar] [CrossRef]
  118. Seronde, M.F.; Vausort, M.; Gayat, E.; Goretti, E.; Ng, L.L.; Squire, I.B.; Vodovar, N.; Sadoune, M.; Samuel, J.L.; Thum, T.; et al. Circulating microRNAs and Outcome in Patients with Acute Heart Failure. PLoS ONE 2015, 10, e0142237. [Google Scholar] [CrossRef] [Green Version]
  119. Bayes-Genis, A.; Lanfear, D.E.; de Ronde, M.W.J.; Lupon, J.; Leenders, J.J.; Liu, Z.; Zuithoff, N.P.A.; Eijkemans, M.J.C.; Zamora, E.; De Antonio, M.; et al. Prognostic value of circulating microRNAs on heart failure-related morbidity and mortality in two large diverse cohorts of general heart failure patients. Eur. J. Heart Fail. 2018, 20, 67–75. [Google Scholar] [CrossRef] [Green Version]
  120. Cakmak, H.A.; Coskunpinar, E.; Ikitimur, B.; Barman, H.A.; Karadag, B.; Tiryakioglu, N.O.; Kahraman, K.; Vural, V.A. The prognostic value of circulating microRNAs in heart failure: Preliminary results from a genome-wide expression study. J. Cardiovasc. Med. 2015, 16, 431–437. [Google Scholar] [CrossRef]
  121. Goren, Y.; Kushnir, M.; Zafrir, B.; Tabak, S.; Lewis, B.S.; Amir, O. Serum levels of microRNAs in patients with heart failure. Eur. J. Heart Fail. 2012, 14, 147–154. [Google Scholar] [CrossRef]
  122. Aydin, S.; Ugur, K.; Aydin, S.; Sahin, I.; Yardim, M. Biomarkers in acute myocardial infarction: Current perspectives. Vasc. Health Risk Manag. 2019, 15, 1–10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Yao, Y.; Du, J.; Cao, X.; Wang, Y.; Huang, Y.; Hu, S.; Zheng, Z. Plasma levels of microRNA-499 provide an early indication of perioperative myocardial infarction in coronary artery bypass graft patients. PLoS ONE 2014, 9, e104618. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. D’Alessandra, Y.; Devanna, P.; Limana, F.; Straino, S.; Di Carlo, A.; Brambilla, P.G.; Rubino, M.; Carena, M.C.; Spazzafumo, L.; De Simone, M.; et al. Circulating microRNAs are new and sensitive biomarkers of myocardial infarction. Eur. Heart J. 2010, 31, 2765–2773. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Widera, C.; Gupta, S.K.; Lorenzen, J.M.; Bang, C.; Bauersachs, J.; Bethmann, K.; Kempf, T.; Wollert, K.C.; Thum, T. Diagnostic and prognostic impact of six circulating microRNAs in acute coronary syndrome. J. Mol. Cell. Cardiol. 2011, 51, 872–875. [Google Scholar] [CrossRef] [PubMed]
  126. Grabmaier, U.; Clauss, S.; Gross, L.; Klier, I.; Franz, W.M.; Steinbeck, G.; Wakili, R.; Theiss, H.D.; Brenner, C. Diagnostic and prognostic value of miR-1 and miR-29b on adverse ventricular remodeling after acute myocardial infarction—The SITAGRAMI-miR analysis. Int. J. Cardiol. 2017, 244, 30–36. [Google Scholar] [CrossRef]
  127. Bauters, C.; Kumarswamy, R.; Holzmann, A.; Bretthauer, J.; Anker, S.D.; Pinet, F.; Thum, T. Circulating miR-133a and miR-423-5p fail as biomarkers for left ventricular remodeling after myocardial infarction. Int. J. Cardiol. 2013, 168, 1837–1840. [Google Scholar] [CrossRef]
  128. Wang, R.; Li, N.; Zhang, Y.; Ran, Y.; Pu, J. Circulating microRNAs are promising novel biomarkers of acute myocardial infarction. Intern. Med. 2011, 50, 1789–1795. [Google Scholar] [CrossRef] [Green Version]
  129. Cheng, Y.; Tan, N.; Yang, J.; Liu, X.; Cao, X.; He, P.; Dong, X.; Qin, S.; Zhang, C. A translational study of circulating cell-free microRNA-1 in acute myocardial infarction. Clin. Sci. 2010, 119, 87–95. [Google Scholar] [CrossRef] [Green Version]
  130. Lv, P.; Zhou, M.; He, J.; Meng, W.; Ma, X.; Dong, S.; Meng, X.; Zhao, X.; Wang, X.; He, F. Circulating miR-208b and miR-34a are associated with left ventricular remodeling after acute myocardial infarction. Int. J. Mol. Sci. 2014, 15, 5774–5788. [Google Scholar] [CrossRef]
  131. Coskunpinar, E.; Cakmak, H.A.; Kalkan, A.K.; Tiryakioglu, N.O.; Erturk, M.; Ongen, Z. Circulating miR-221-3p as a novel marker for early prediction of acute myocardial infarction. Gene 2016, 591, 90–96. [Google Scholar] [CrossRef]
  132. Liu, X.; Dong, Y.; Chen, S.; Zhang, G.; Zhang, M.; Gong, Y.; Li, X. Circulating MicroRNA-146a and MicroRNA-21 Predict Left Ventricular Remodeling after ST-Elevation Myocardial Infarction. Cardiology 2015, 132, 233–241. [Google Scholar] [CrossRef] [PubMed]
  133. Xiao, J.; Gao, R.; Bei, Y.; Zhou, Q.; Zhou, Y.; Zhang, H.; Jin, M.; Wei, S.; Wang, K.; Xu, X.; et al. Circulating miR-30d Predicts Survival in Patients with Acute Heart Failure. Cell. Physiol. Biochem. 2017, 41, 865–874. [Google Scholar] [CrossRef] [PubMed]
  134. Huang, C.K.; Kafert-Kasting, S.; Thum, T. Preclinical and Clinical Development of Noncoding RNA Therapeutics for Cardiovascular Disease. Circ. Res. 2020, 126, 663–678. [Google Scholar] [CrossRef] [PubMed]
  135. Weinberger, F.; Mannhardt, I.; Eschenhagen, T. Engineering Cardiac Muscle Tissue: A Maturating Field of Research. Circ. Res. 2017, 120, 1487–1500. [Google Scholar] [CrossRef] [PubMed]
  136. Mannhardt, I.; Breckwoldt, K.; Letuffe-Breniere, D.; Schaaf, S.; Schulz, H.; Neuber, C.; Benzin, A.; Werner, T.; Eder, A.; Schulze, T.; et al. Human Engineered Heart Tissue: Analysis of Contractile Force. Stem Cell Rep. 2016, 7, 29–42. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Prondzynski, M.; Lemoine, M.D.; Zech, A.T.; Horvath, A.; Di Mauro, V.; Koivumaki, J.T.; Kresin, N.; Busch, J.; Krause, T.; Kramer, E.; et al. Disease modeling of a mutation in alpha-actinin 2 guides clinical therapy in hypertrophic cardiomyopathy. EMBO Mol. Med. 2019, 11, e11115. [Google Scholar] [CrossRef]
  138. Bellera, N.; Barba, I.; Rodriguez-Sinovas, A.; Ferret, E.; Asin, M.A.; Gonzalez-Alujas, M.T.; Perez-Rodon, J.; Esteves, M.; Fonseca, C.; Toran, N.; et al. Single intracoronary injection of encapsulated antagomir-92a promotes angiogenesis and prevents adverse infarct remodeling. J. Am. Heart Assoc. 2014, 3, e000946. [Google Scholar] [CrossRef] [Green Version]
  139. Foinquinos, A.; Batkai, S.; Genschel, C.; Viereck, J.; Rump, S.; Gyongyosi, M.; Traxler, D.; Riesenhuber, M.; Spannbauer, A.; Lukovic, D.; et al. Preclinical development of a miR-132 inhibitor for heart failure treatment. Nat. Commun. 2020, 11, 633. [Google Scholar] [CrossRef]
  140. Batkai, S.; Genschel, C.; Viereck, J.; Rump, S.; Bar, C.; Borchert, T.; Traxler, D.; Riesenhuber, M.; Spannbauer, A.; Lukovic, D.; et al. CDR132L improves systolic and diastolic function in a large animal model of chronic heart failure. Eur. Heart J. 2021, 42, 192–201. [Google Scholar] [CrossRef]
Cells 11 00983 g001 550
Figure 1. Schematic diagram depicting miRNAs orchestrating myocardial cell apoptosis, necrosis, and autophagy in myocardial infarction.
Figure 1. Schematic diagram depicting miRNAs orchestrating myocardial cell apoptosis, necrosis, and autophagy in myocardial infarction.
Cells 11 00983 g001
Table
Table 2. Diagnostic relevance of miRNA in acute myocardial infarction and heart failure.
Table 2. Diagnostic relevance of miRNA in acute myocardial infarction and heart failure.
DiseasemiRNAExpressionReferences
Myocardial InfarctionmiR-1Upregulation[115,118]
miR-21Upregulation[121]
miR-29bUpregulation[115]
miR-133Upregulation[113,114]
miR-208bUpregulation[119]
miR-221-3pUpregulation[120]
miR-328Upregulation[117]
miR-423Upregulation[116]
miR-499Upregulation[112,113]
Heart FailuremiR-18aUpregulation[122]
miR-21Upregulation[123]
miR-26bUpregulation[124]
miR-30cUpregulation[125]
miR-30dDownregulation[126]
miR-126Downregulation[127]
miR-182Upregulation[128]
miR-210Upregulation[129]
miR-223Downregulation[122]
miR-423Downregulation[130]
miR-499Upregulation[131]
miR-652Downregulation[122]
miR-1254Upregulation[132]
miR-1306Downregulation[133]
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Kansakar, U.; Varzideh, F.; Mone, P.; Jankauskas, S.S.; Santulli, G. Functional Role of microRNAs in Regulating Cardiomyocyte Death. Cells 2022, 11, 983. https://doi.org/10.3390/cells11060983

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Kansakar U, Varzideh F, Mone P, Jankauskas SS, Santulli G. Functional Role of microRNAs in Regulating Cardiomyocyte Death. Cells. 2022; 11(6):983. https://doi.org/10.3390/cells11060983

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Kansakar, Urna, Fahimeh Varzideh, Pasquale Mone, Stanislovas S. Jankauskas, and Gaetano Santulli. 2022. "Functional Role of microRNAs in Regulating Cardiomyocyte Death" Cells 11, no. 6: 983. https://doi.org/10.3390/cells11060983

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