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28 January 2022

Role of miRNA-1 and miRNA-21 in Acute Myocardial Ischemia-Reperfusion Injury and Their Potential as Therapeutic Strategy

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and
Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at UCLA, BH-550 CHS, Los Angeles, CA 90095, USA
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Author to whom correspondence should be addressed.
Int. J. Mol. Sci.2022, 23(3), 1512;https://doi.org/10.3390/ijms23031512
This article belongs to the Special Issue MicroRNA in Cardiac Health and Disease
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Abstract

Coronary artery disease remains the leading cause of death. Acute myocardial infarction (MI) is characterized by decreased blood flow to the coronary arteries, resulting in cardiomyocytes death. The most effective strategy for treating an MI is early and rapid myocardial reperfusion, but restoring blood flow to the ischemic myocardium can induce further damage, known as ischemia-reperfusion (IR) injury. Novel therapeutic strategies are critical to limit myocardial IR injury and improve patient outcomes following reperfusion intervention. miRNAs are small non-coding RNA molecules that have been implicated in attenuating IR injury pathology in pre-clinical rodent models. In this review, we discuss the role of miR-1 and miR-21 in regulating myocardial apoptosis in ischemia-reperfusion injury in the whole heart as well as in different cardiac cell types with special emphasis on cardiomyocytes, fibroblasts, and immune cells. We also examine therapeutic potential of miR-1 and miR-21 in preclinical studies. More research is necessary to understand the cell-specific molecular principles of miRNAs in cardioprotection and application to acute myocardial IR injury.

1. Introduction

Coronary artery disease remains the leading cause of death for both men and women of most ethnicities in the United States [1,2]. Roughly 659,000 Americans die from heart disease annually: accounting for one in every four deaths [3]. Acute myocardial infarction (MI) is characterized by decreased blood flow to the coronary arteries, resulting in pathological states in the myocardium, including mitochondrial dysfunction and, if continued, cardiomyocytes death [4]. The most effective strategy for treating an MI is early and rapid myocardial reperfusion via thrombolytic agents or percutaneous coronary intervention (PCI) [5]. However, restoring blood flow to the ischemic myocardium can induce further damage, known as ischemia-reperfusion (IR) injury. Mitochondria, the main energy reservoirs of cells, play a critical role in cellular function and vitality in the heart. Cells of ischemic hearts switch from aerobic respiration to anaerobic glycolysis for ATP production. As a result, intracellular levels of calcium and sodium rise and, if continued, leads to prolonged ischemia [4]. When reperfusion occurs in an ischemic heart, these ischemic conditions worsen to drive mitochondrial damage, ensuing cell death [4]. As a result, dead tissue accumulates in the myocardium and contributes to the increase in the infarct size over time [4]. Thus, myocardial reperfusion is a “double edge sword” due to its paradoxical nature to protect as well as damage the heart [6].
Novel therapeutic strategies are critical to limit myocardial IR injury and improve patient outcomes following reperfusion intervention. The ischemic mediators of myocardial reperfusion injury operate within the first few minutes of myocardial reperfusion, offering a tight therapeutic window for reducing MI size in patients undergoing PCI. A clear understanding of IR injury mechanisms is needed to overcome barriers to developing a safe and effective therapeutic agent. microRNAs (miRNAs) are promising candidates to modulate the molecular and cellular processes involved in IR injury. miRNAs are small non-coding RNA molecules (~22 nucleotides in size) that have been implicated in attenuating IR injury pathology in pre-clinical rodent models [4]. The main function of miRNAs is to promote degradation and inhibit the translation of protein-coding genes by annealing to target mRNAs [7,8]. Each miRNA may modulate 10–100 s of mRNA genes and thus can control multiple cellular pathways at once. Additionally, miRNAs can exist as clusters in the mammalian genome and be transcribed as polycistronic primary transcripts. The purpose of the miRNA clusters is to potentially regulate every aspect of cellular function, including growth, development, cell death, among others [9]. Overall, these miRNAs have a profound impact on cardiac pathology and, when dysregulated, contribute to the disease, as is the case in acute myocardial IR injury [10,11,12]. miRNAs are favorable therapeutic strategies as they can be targeted with high affinity and specificity. In addition to emerging as potential therapeutic regulators of IR injury, miRNAs can also be excreted from cells into the circulation and act as versatile endogenous signals [13,14]. Thus, miRNAs could serve as biomarkers to detect and determine risk profiles for IR injury in vulnerable MI patients [15,16,17].
miRNAs are extensively involved in molecular pathways of cardiac diseases related to IR injury, including arrhythmia triggered after an MI [18] as well as atherosclerosis or obesity, which predisposes patients to MI [13]. Thus, miRNAs dysregulated in the whole disease process (atherosclerosis, MI and IR injury) would make more attractive therapeutic targets than miRNAs only dysregulated in one aspect of the disease. By this rationale, for this review, an independent analysis using HMDD (the Human microRNA Disease Database, V3.2) [19,20] identified miRNA-1 (miR-1) and miRNA-21 (miR-21) as top hits of multiple cardiovascular disease states in the context of IR injury.
Cardiac cell types can differentially express miRNAs during disease onset and progression. Several databases, including the previously mentioned HMDD, have successfully mapped miRNA expression profiles to specific cell types and identified their downstream targets. The purpose of mining these big data tools is to identify miRNAs that are differentially expressed in human cardiovascular disease (CVD) and also discover any shared signatures among related diseases. Despite many research efforts thus far, it remains unclear whether any miRNAs protect the heart from IR injury in humans. Here, we will highlight the most recent molecular perspectives of the mechanistic and therapeutic roles miR-1 and miR-21 play in IR injury and related cardiac diseases.

3. Role of miR-1 and miR-21 in Different Cell Types of IR Injured Hearts

3.1. Single-Cell Sequencing Data on IR Injury

Existing therapies to salvage the myocardium following an MI mainly focus on revascularizing the blocked artery. However, the adult human heart cannot fully heal or regenerate after cardiac injury, which contributes to the irreparable loss of cardiomyocytes [75]. With fewer myocytes, the injured heart remodels aberrantly and fails to contract efficiently [76,77]. Many cells, including fibroblasts and endothelial cells, change phenotype, whereas neutrophils, macrophages, lymphocytes are recruited to sites of myocardial injury to jumpstart the healing process [78,79,80,81]. Two physiological functions dictate a healthy heart: the ability for cells to communicate and coordinate with each other [76]. Overall, four related phases highlight cardiac remodeling post-MI and involve all these cells: inflammatory, proliferative, maturation, and remodeling phases [77]. The first phase, inflammatory, is triggered by a loss of myocytes at the site of infarct. In response, endothelial cells would enhance vascular permeability to immune cells that assist with removing dead cells in the infarcted site. In the proliferative phase, inflammatory responses fade as macrophages switch phenotype and repair mechanisms become dominant. Next, fibroblasts and endothelial cells multiply, lay down collagen, and create a microvascular bed in the dead myocardium. In the maturation phase, activated fibroblasts replace the damaged heart muscle with the scar by secreting ECM proteins. Lastly, the damaged heart undergoes pathological remodeling.
Recently, high throughput single-cell RNA sequencing (scRNAseq) reveals differentially expressed genes in cardiac cell types of IR injured mammalian hearts [82]. From such data, the ability to study the role of various types of cells during wound healing response following IR is possible. Additionally, these data can help link changes in gene expression to changes in cell function and explain cellular interactions relevant for cardiac repair.
Molenaar et al. used a FACS-based scRNA-seq approach to outline cellular distribution, biological role and crosstalk following IR injury to the adult heart [83]. Neutrophils were present in early times of cardiac injury, while fibroblasts and macrophages were detected mid-time point and declined as injury continued long-term [83]. Furthermore, functional data using differentially expressed genes suggest a switch in fibroblasts and macrophages to anti-inflammatory and pro-repair/angiogenic types. These cellular switches were consistent with recent bulk-RNA sequencing performed on the whole heart tissues [84,85]. In both studies, [83,84] the authors found that the transcriptional profile of macrophages was a continuum—from day 0 to day 7—from a more pro-inflammatory phenotype toward a more pro-resolving phenotype. In addition, both studies highlight the need to redefine our M1/M2 macrophages phenotypic definition as they both found that the arginase—an archetypal marker of M1 phenotype—is up-regulated (900-fold) at day 1. Thus, these studies challenge our conventional view of an almost pure M1 macrophages population at early stage moving toward an exclusive M2-macrophages later on, as well as our current definition of M1/M2 macrophages phenotype. Although previously studied at single-cell scale [86,87,88,89], a detailed analysis of how exactly these cell types behave during cardiac repair will prove necessary to develop impactful treatments for IR injury.

3.2. Role of miR-1 and miR-21 in Cardiac Cell Types Post-MI

3.2.1. Cardiomyocytes

Cardiomyocytes, high energy-demanding cells, give the ability for the heart to contract and perform mechanical pumping. In IR injury, cardiomyocytes become vulnerable to death following a lack of blood supply [90]. A major approach is to therapeutically target miRNAs that prevent cardiomyocyte cell death after ischemic-reperfusion stress.
Liu et al. explain the effects of miRNAs on cell types and expand on molecular roles of miRNAs that control cell-specific actions [76]. miR-1 and miR-21 were identified to mediate components of apoptosis pathways in injured cardiomyocytes during MI. miR-1 directly inhibits the anti-apoptotic protein Bcl-2 in cardiomyocytes of the IR injury rat model [38]. The data reveal that miR-1 is important to regulate cardiomyocyte apoptosis, which entails post-transcriptional repression of Bcl-2 [38]. Another pathway implicated in cardiomyocyte apoptosis include anti-apoptotic protein kinase C epsilon (PKCε) [76]. In cardiomyocytes, miR-1 worsened ischemia-reperfusion injury in in vivo mouse models [30]. Pan et al. identified PKCε and HSP60 as suppressed miR-1 molecular targets in the cardiac injury pathways involving apoptosis [30]. In summary, the study showed that miR-1 is a causal miRNA for cardiac injury and systemic LNA-antimir-1 therapy prevents this condition [30]. One last notable pathway mediating apoptosis involves the molecule programmed cell death 4 (PDCD4), which increases in expression during apoptosis and functions as proapoptotic inhibitor of genes [76]. miR-21 directly inhibits PDCD4 signaling and prevents apoptosis in cardiomyocytes during MI [70,71]. Altogether, the therapeutic application of miR-1 and miR-21 in heart disease related to ROS such as MI and myocardial IR injury is to prevent cardiomyocyte cell death (Figure 2).
Figure 2. Overview of Action of miR-1 and miR-21 on Cardiomyocytes, Fibroblasts, and Immune Cells in Hearts Subjected to I/R Injury. In cardiomyocytes, inhibition of miR-1 prevents apoptosis via Bcl-2 and PKC, whereas miR-21 inhibits apoptosis via PDCD4. In cardiac fibroblasts, inhibition of miR-21 prevents TGF-β signaling and ECM synthesis via SMAD7, TGFβIII, or SPRY1. In immune cells, miR-21 regulates multiple aspects of macrophage function, including inhibition of cytokine production and activation of macrophage polarization through P38, NF-kB. Created with BioRender.com.

3.2.2. Fibroblasts

Cardiac fibroblasts become activated following MI and differentiate into myofibroblasts, which form scars that resist ventricular wall rupture. The continuous activation of cardiac fibroblasts, proliferation, and ECM deposition after MI results in pathological cardiac fibrosis, which can worsen the injury and elicit heart failure [76]. miRNAs are a therapeutic approach that can reverse the activated phenotype to dampen cardiac fibrosis.
Transforming growth factor-β (TGF-β) is a key regulator in fibroblast repair of heart after MI [91], and signaling rely on proteins such as decapentaplegic homologs (SMADs). TGF-β decreases MMPs [92] and, at the same time, increases the generation of collagen type 1 and 3, leading to ECM production [93]. TGF-β receptor III (TGFβIII) is a known negative regulator of TGF-β signaling [94]. Liang et al. explain a reciprocal loop in MI-induced cardiac fibrosis in mice by which TGF-β upregulates miR-21, which subsequently downregulates TGFβIII [95]. miR-21 inhibition of TGFβIII increases collagen secretion by high TGF-β release and phosphorylated-Smad3 [95]. The study proposes miR-21 and TGFβIII pathway as a potential target to prevent and treat myocardial remodeling after MI. TGF-β signaling is inhibited by SMAD-7; thus, anti-miRNAs against this SMAD can prevent fibrosis. In a study, miR-21 regulates myocardial fibrosis after MI in mice by suppressing SMAD7. The findings suggest that miR-21 is important for cardiac fibroblast activation and fibrosis after MI by acting on TGF-β/Smad7 signaling (Figure 2). The Thum lab established the harmful role of miR-21 in cardiac fibrosis [65]. In cardiac fibroblasts, miR-21 revamps the structure and function of failing mice hearts by modulating the ERK-MAP kinase signaling pathway via inhibition of Spry1 [65]. In vivo blocking of miR-21 by antagomir will lower ERK-MAP kinase activity, repress fibrosis and enhance cardiac function [65].

3.2.3. Immune Cells

MI gives rise to a heightened immune response beginning with an acute pro-inflammatory response, which is taken over by an anti-inflammatory reparative state. The goal of miRNA therapeutics is to weaken the initial inflammatory response and promote the reparative phase.
One factor that governs the advancement and degree of tissue remodeling is the buildup of pro-inflammatory cytokines. The severe inflammation initiated by damage-associated molecular patterns (DAMP) in macrophages explains the development of cardiac dysfunction and remodeling. Thus, a therapy that successfully blocks this process could decrease MI size and enhance cardiac function. miR-21 mimic given to monocytes macrophages in mice reduced inflammatory cytokine expression by targeting KBTBD7 and inhibiting P38 and NF-kB signaling in myocardium post-MI (Figure 2) [96]. miR-21 fine-tunes the mechanisms involved in inflammation triggered by MI.
While acting on different cells in the heart, both miR-1 and miR-21 have harmful roles in the progression of MI. To date, more studies are needed to support the clinical translation of miRNA therapies to treat post-MI complications.

3.3. Studies Integrating mRNA Expression Data from Single-Cell with miRNAs Evident in IR Injury

For the past decade, high throughput single-cell RNA sequencing (scRNAseq) technologies can generate meaningful mRNA expression profiles for cells. The purpose of scRNseq is to understand the complex role of cells in disease pathology and propose new therapeutic targets. However, miRNAs cannot be captured by single-cell gene expression assays and thus, studied to the same degree. An effective workaround method, premises of miReact software, infers miRNA activity estimates from scRNAseq data by relying on their predefined binding sequence motifs and downstream genes [97].
The advances to derive cell-specific miRNA activity in single-cell data have unlocked the potential to study rare cell types. Per analysis of mouse and human scRNA data, miR-1 activity was specific to cardiac muscle cells [97] and, this was consistent with findings in bulk RNA sequencing data sets and the literature [98]. miR-1 specificity to cardiac cells has the potential to aid in reducing the disease burden. However, this technique is still in its infancy, and more research needs to be performed.

4. Therapeutic Potential of miRNAs in IR Injury

Over the years, experimental evidence supports miRNAs to have cell-specific regulatory roles in cardiac pathophysiology. However, the clinical translational value of miRNAs as therapeutic targets in cardiovascular disease is yet to be determined.

4.1. Modes of miRNA Therapy Delivery

miRNAs control gene expression in up to 90% of the human genome by directly binding to their target genes, mRNA [99]. The expression of miRNAs not only differs between healthy and IR injured hearts but is also dependent on the cell types involved. miRNA therapy needs to involve a delivery system that is effective and also, specific to cell types in the heart. Successful delivery of miRNAs is dependent on overcoming several challenges: intrinsic instability of miRNAs in circulation, off-target effects, and poor distribution [100,101]. miRNAs are compact, hydrophilic molecules that can be administered intravenously or subcutaneously [102]. Yet, the clinical applicability of miRNAs is limited because these single-stranded, open-ended molecules are susceptible to enzymatic degradation or renal excretion [103].
A well-established way to silence miRNAs in disease models is to utilize classical antagomirs [104]. Antagomirs, single-stranded RNA inactivator molecules, work by hybridizing to target miRNA via complementary base pairing. In order to have an effect, antagomirs must have key chemistry properties: cell permeability, slow excretion rate, stability in an animal’s body, and interact with miRNA with great specificity and affinity [105,106,107]. With existing technology, locked nucleic acids (LNA) or 2′-O-methyl group (OME) are popular options that chemically modify miRNAs, increasing their stability [15,104]. Upon cellular uptake, these molecules can cause significant knockdown of miRNAs and effectively resolve experimentally induced cardiac pathology [65].
In contrast to antagomirs, synthetic RNA duplexes called agomirs can be used to mimic the endogenous functions of a particular miRNA. Similar to antagomirs, agomirs need to be chemically modified to enhance stability and cellular uptake. The strand that is identical to miRNA of interest is the “guide,” while the strand that is modified with cholesterol is the “passenger” [104]. These molecular mimics effectively restore low levels of miRNA driven by pathology, but problematic because high levels of that miRNA accumulate in off-target tissues [104].
Viral vectors, delivery vehicles for miRNAs, are a good way to increase stability during transport, and viral capsids can be altered to target specific tissues [102]. Adeno-associated viruses (AAV), which continuously express the miRNA of interest, have high specificity towards the heart and meet safety standards in clinical gene therapy trials [104]. However, AAV has potential downsides such as unwanted immune activation and incorporation of the virus into the host genome [102]. Other forms of delivery, such as liposomes, lipid-based vectors, protect the miRNA from enzymatic degradation [103]. An enticing option is exosomes, natural carriers of miRNAs because these can deliver miRNA to specific types of cells by receptor-mediated binding and also quickly taken into cells to minimize off-target effects [108]. While other delivery strategies such as nanoparticles [109], “passive-drug targeting” [103], and mesenchymal stem cell-derived extracellular vesicles (MSC-EV) [110] are showing promising results, more research is needed for clinical use.

4.2. Potential Benefits of Delivering miRNA Therapies Post-MI

Increasingly, CVD-related research has focused on discovering various cardioprotective interventions that target IR injury associated with atherosclerosis and MI. The targets used for cardioprotective interventions come from mechanistic studies conducted in mice and humans. miR-1 and miR-21 are potential molecular targets or mediators of cardioprotection against IR injury. This section aims to briefly outline the potential role of miR-1 and miR-21 in therapeutic approaches, including the delivery of miR mimics.
Yin et al. found that mice subjected to cytoprotective heat shock (HS) can upregulate miR-1 and miR-21 in the heart [62]. miRs isolated from HS mice and injected into non-HS mice significantly reduced the infarct size following IR injury. Similarly, the chemically synthesized exogenous miR-21 was cardioprotective [62]. However, miR-21 induced protection stopped when mice were co-treated with miR-21 inhibitor [62]. The use of endogenous miRs as therapy is favorable over other exogenous agents for several reasons. Firstly, endogenous miRs are natural products, thus non-toxic to cells. Secondly, natural conditions (e.g., hyperthermia) can induce endogenous miRs in vivo. Lastly, miRs can easily move across sub-cellular structures due to their small size. Therefore, the precise role of endogenous miRs in the heart may serve as a cardioprotective agent in patients that develop advanced atherosclerosis and subsequent MI.
As mentioned previously, miR-based therapy can target different cell types in the heart and potentially protect against MI. Bejerano et al. explored whether high levels of miR-21 transcript in macrophage-enriched regions of the infarcted heart could switch their phenotype from an inflammatory (M1) to a reparative (M2) subsequently resolving inflammation and promoting repair in the heart [111]. The nanoparticle delivery of miR-21 mimic to cardiac macrophages improved myocardial remodeling after MI, shown by high angiogenesis, low hypertrophy, fibrosis, and apoptosis [111]. In this study, the laser capture microdissection (LCM) enabled to research macrophages in their natural microenvironment without the need for in vitro cell culture or processing studies [111]. Thus, the delivery of miR mimic, when used with approaches such as LCM, is crucial for evaluating changes in cell phenotypes following cardiac injury.
While extensive research has shown associations between miRs and IR injury, their therapeutic potential as targets is inconclusive. The majority of the studies, as highlighted in Table 1, do not have a clear acceptance of the role of miR-1 and miR-21 in IR injured hearts. Possibly, the changes in expression of miRs are also dependent on the type of cells involved in IR injury. Thus, a more informed view of these two miRs would be possible with next-generation therapeutic and predictive approaches. To date, whether miR-1 and mR-21 studies will be translated to clinical application is unresolved but continues to be promising.

5. Concluding Remarks

miRNAs are powerful regulators either beneficial or harmful to acute myocardial IR injury and related cardiac diseases. The complex modulatory roles of miR-1 and miR-21 may be heavily dependent on the types of cells involved in each cardiac disease. In order to effectively translate miRNA-based cardiovascular therapies to the clinic, more concrete knowledge of mechanisms of miRNA effects on each cardiac cell type has to be clearly elucidated. Although limited by technology, the focus to design cell-specific miRNAs is emerging as effective methods to treat cardiovascular disease. However, clinical translation of these therapies will require better administration protocols, cell-specific delivery, and additional prognostic models.

Author Contributions

E.J. drafted the article. E.J., L.M., G.R. and M.E. revised the article for significant intellectual content. E.J. generated the figure. E.J. and M.E. revised the figure. All authors gave final permission for publication. All authors have read and agreed to the published version of the manuscript.

Funding

The work was funded by the National Institutes of Health: R01HL159865 and R01HL147586 (M.E.).

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

MImyocardial infarction
PCIpercutaneous coronary intervention
IRischemia-reperfusion
miRNAsmicroRNAs
miR-1miRNA-1
miR-21miRNA-21
CVDcardiovascular disease
Cx43connexin 43
Irx5iroquois homeobox domain 5
KCND2potassium voltage-gated channel subfamily D member 2
EPCsendothelial progenitor cells
ROSreactive oxygen species
PDCD4programmed cell death 4
scRNAseqsingle-cell RNA sequencing
M1pro-inflammatory macrophage
M2anti-inflammatory macrophage
PKCεprotein kinase C epsilon
TGF-βtransforming growth factor-β
SMADsdecapentaplegic homologs
TGFβIIITGF-β receptor III
DAMPdamage-associated molecular patterns
LNAlocked nucleic acids
OME2′-O-methyl group
AAVadeno-associated viruses
MSC-EVmesenchymal stem cell-derived extracellular vesicles
miR-133miRNA-133

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