Highlighting Exosomes’ Function in Cardiovascular Diseases

Abstract

Exosomes, as one of the extracellular vesicles’ subgroups, played an important role in the cell to cell communication. The cargos and surface protein of exosomes have been known to affect the cardiovascular system both positively and negatively in chronic heart failure, ischemic heart disease, and atherosclerosis. There have been several exosomes that emerged as potential diagnostic and prognostic markers in cardiovascular patients. However, the conditions affecting the patients and the method of isolation should be considered to create a standardized normal value of the exosomes and the components. CPC-derived exosomes, ADSCs-derived exosomes, and telocyte-derived exosomes have been proven to be capable of acting as a therapeutic agent in myocardial infarction models. Exosomes have the potential to become a diagnostic marker, prognostic marker, and therapeutic agent in cardiovascular diseases.

1. INTRODUCTION

Exosomes, the smallest subgroup of extracellular vesicles (30-150 nm, compared to microvesicles 0.1-1 µm and apoptotic bodies 1-5 µm), are released from different cells and played an important role in intercellular communication [1, 2]. Cardiac myocyte, cardiac fibroblast, endothelial cells, cardiac progenitor cells, adipocytes, and cardiac telocytes are cardiac cells known to be releasing the exosomes [3, 4]. Exosomes as a messenger cannot be separated from the proteins, lipids, and nucleic acids contained inside of them because it can determine the cell origin releasing the exosomes [1]. These cargos have a unique ability to alter the function and behavior of the target cells [5]. Therefore, this article aims to discuss further the diagnostic, prognostic, and therapeutic role of exosomes in cardiovascular disease.

2. BIOGENESIS OF EXOSOMES

Exosomes are differently formed than the other subgroup of extracellular vesicles. The blebs or dying cells formed apoptotic bodies, outward budding of the plasma membranes formed microvesicles, and the invagination of plasma membrane formed exosomes [6]. It is followed by the budding of payload into the endosomal membrane to form multivesicular endosome (MVE) or also known as the multivesicular body (MVB). After going into maturation through acidification, MVB fuses with the plasma membrane and releases the exosomes [6, 7]. However, only MVBs that are more enriched in cholesterol go into the process, while other MVBs less enriched in cholesterol go into lysosomal degradation inside the cell [6].

The selection of exosome cargo is not yet well understood, even though it seems that the selection is managed by endosomal sorting complexes required for transport (ESCRT) [4]. Besides ESCRT, Groot M et al. suggested that there are RNA-Binding Protein (RBP) and membrane protein [8]. Both are responsible for the sorting process of RNA as exosomes’ cargos. In addition, membrane protein may affect the sorting process directly (by affecting the RNA) and indirectly (by affecting the RBP). The indirect sorting process by membrane protein was done by Caveolin-1, which affected the level of hnRNP. The existence of the two proteins that control the cargo sorting process supported the previous idea that exosomes’ content/cargo did not occur spontaneously [8]. Membrane proteins are proteins located in the plasma membrane. The presence of membrane proteins suggested that the sorting process of the exosomes’ content may occur from the beginning of the exosomes’ formation since the invagination of the plasma membrane. The sorting process was then completed intracellularly with the help of RBPs. The RBPs known are Heterogeneous Nuclear Ribonulceoproteins (hnRNPs), Argonaute 2, Y-Box Binding Protein 1 (YBX-1), MEX3C, Major Vault Protein, and La Protein, while membrane proteins currently known are Caveolin-1, Neural Sphingomyelinase 2, and Vacuolar Protein Sorting-Associated Protein 4 [8]. Zhang J et al. also suggested 3 same proteins responsible for the sorting process; neural sphingomyelinase 2, hnRNP, and miRNA induced silencing complex (miRISC)-related pathway (correlated with Argonaute 2), but added 1 different sorting mechanism which is 3’-end of the miRNA sequence-dependent pathway. The prior sorting mechanism preferred miRNAs with more poly(U) than poly(A) at the 3’-end to be sorted into the exosomes [9]. Each protein (RBP and membrane protein) affected specific RNA to be sorted into the exosomes [8, 9]. The summary of exosome biogenesis can be seen in Fig. (1).

Fig. (1).

Exosomes biogenesis. The process begins with membrane invagination. Next, the less cholesterol enriched membrane will go on the lysosomal pathway, while the more cholesterol enriched membrane will go on the exosomal pathway. The more cholesterol enriched membrane formed will be filled with smaller membranes (exosomes) and different cargos, including miRNA, lipid, and protein. The sorting process of lipid and protein remains unknown. On the other hand, miRNA is sorted with the help of RNA binding protein (RBP), membrane protein (MP), ESCRT, and 3’-end of the miRNA sequence-dependent pathway. Membrane protein can sort the miRNA directly and indirectly (by affecting RBP levels). The indirect sorting process by membrane protein was done by Caveolin-1, which affected the level of hnRNP. The multivesicular bodies (MVB) will then go on maturation through acidification. Finally, the membrane of MVB will fuse with the cell membrane and release exosomes. (A higher resolution / colour version of this figure is available in the electronic copy of the article) .

From the two previous studies, we figured that miR-133 is sorted by YBX-1 and miR-93 is sorted by hnRNPA2B1. miR-133, miR-93, and other components of exosomes that are associated with cardiovascular diseases will be further discussed in this article review. Despite the fact that RBP and membrane protein involved deeply in the sorting process of RNA, the exact impulse that affected the levels of RBP and membrane protein remain unclear. Furthermore, the sorting process of the other contents of exosomes (beside RNA) remained unknown. Thus, further research can be conducted to fill the gap of understanding; especially the sorting mechanism of other miRNAs that was associated with cardiovascular diseases and the sorting process of other contents/cargos of exosomes.

3. ISOLATING EXOSOME

The methods of exosome isolation have grown rapidly even though currently, no method can be considered to be perfect. There are various techniques to isolate exosomes such as ultracentrifugation, size-based filtration, size-exclusion chromatography, polymer precipitation, immunoaffinity purification, and microfluidics-based isolation techniques. Besides, there are some commercial kits for exosomes available in the market such as ExoQuick Exosome Precipitation, Total Exosome Isolation, and exoRNeasy Serum/Plasma kit. Each of these methods has specific advantages and disadvantages that needed to be considered before using it [7, 10].

4. EXOSOMES AND CARDIOVASCULAR DISEASES

4.1. Chronic Heart Failure (CHF)

There have been several trials (in animals and humans) that proved the involvement of exosomes in CHF pathogenesis. The study by Ye et al. found that there were more exosomes in patients with chronic heart failure than in normal patients. Furthermore, the plasma-derived exosomes carried mtDNA, which the authors suggest triggered an inflammatory response via the TLR9-NF-κB pathway [11]. This finding aligned with the previous findings, which showed that chronic inflammation is related to the progression and worsening prognosis of chronic heart failure [12, 13].

Nie et al. conducted in vivo and in vitro study to find the correlation between miR-217 and cardiac hypertrophy and dysfunction. In the in vivo study, the authors found that miR-217 in exosomes is overexpressed in the hearts of CHF patients and aggravates pressure overload-induced cardiac hypertrophy and dysfunction by suppressing PTEN expression. However, there was no difference between the plasma miR-217 levels from the CHF patients and control. It was then supported by the in vitro study using the cardiomyocyte exosomes, where the authors found that cardiomyocyte-derived miR-217-containing exosomes induce fibroblast proliferation and may promote cardiac fibrosis. The in vivo and in vitro study suggest that miR-217 may play roles in cardiac hypertrophy and dysfunction [14].

The research conducted by Lyu et al. suggested a different correlation among the Angiotensin II (AngII), exosomes, and cardiomyocyte hypertrophy. It revealed that AngII could stimulate cardiac fibroblasts to release exosomes, which then acts as a paracrine mediator upregulating Renin, Agt, AT1R, and AT2R while also downregulating ACE2 in cardiomyocytes. As a consequence, the autocrine activation of the AngII-AT1R axis was intensified and led to pathological cardiomyocyte hypertrophy [15]. The study was supported by the fact that AngII-treated myocyte supernatant had significantly higher exosomal protein concentration than the control. Besides the higher exosomal protein concentration, the expression of heat shock protein 90 (HSP90) and IL-6 increased significantly in myocyte derived exosomes. The authors proposed that HSP90 orchestrated the synthesis of IL-6 and its release in exosomes from myocytes during cardiac hypertrophy [16].

4.2. Ischemic Heart Disease

Exosomes as messengers in the cell to cell communication play an important role during cardiac remodeling post-myocardial infarction (post-MI). They are responsible for the surviving cardiac cells’ communication with nearby or distant cells to maintain homeostasis and promote cardiac repair through angiogenesis [17]. Hao et al. conducted in vivo and in vitro research to find the role of exosomes. In the in vitro research, the researcher found that coronary serum exosomes from patients with myocardial ischemia (isc-EXO) and healthy (con-EXO) both promoted endothelial cell proliferation. They also found that coronary serum exosomes from patients with myocardial ischemia (isc-EXO) were better in angiogenesis-related processes, including proliferation, migration, and tube formation, compared to coronary serum exosomes from healthy patients (con-EXO). The in vivo research was conducted using a mouse hind-limb ischemia model to confirm the in vitro research findings. The isc-EXO group showed a significantly 2-fold higher blood perfusion than the con-EXO group 21 days post-injection. The muscle of the limb was harvested and the isc-EXO group showed a significantly higher capillary density compared to the con-Exo group. Both in vitro and in vivo analyses showed that isc-EXO was able to enhance angiogenesis compared to con-EXO. Furthermore, the researcher found that miR-939-5p was less expressed in isc-EXO and found it inhibiting iNOS expression and ability, which impaired angiogenesis [18].

4.3. Atherosclerosis

A rat model of high fat diet-induced atherosclerotic showed that circulating levels of oxidized-LDL and homocysteine raised on 2 weeks and heat shock protein 70 (HSP70) levels were not elevated until 4 weeks after the high fat diet. At the same time as the elevation of HSP70 levels, morphological studies showed the adhesion of monocytes to the endothelium. Referring to the facts received during the trial, R. Zhan et al. suggested that exosome-dependent HSP70 might play an important role in the pathogenesis of atherosclerosis as pro-atherosclerotic factor [19].

Non-coding small RNAs or known as micro-RNA (miR) was known for their role in atherosclerotic progression and regression [20]. One of them was exosome-mediated miR-155. When it is transferred from muscle cells to endothelial cells, it may bring a harmful effect to the endothelial cells. This movement may cause endothelial injury and promote atherosclerosis [21]. Contrary to the previous findings, miR-10a reduced the magnitude of inflammation and shifted monocyte activation toward immunomodulatory response by suppressing proinflammatory genes BTRC, MAP3K7 IRAK4 [22].

4.4. Cardioprotective

Ischemia-Reperfusion Injury (IRI) risk was linked to early reperfusion within the percutaneous coronary intervention (PCI) procedure. Previously, experimental studies have shown that IRI can be reduced with ischemia post-conditioning but most of the studies assumed that cardiomyocytes were the target of it. The research conducted by Hui et al. targeted a different target, cardiac fibroblast, and found that microRNA-423-3p exosomes derived from cardiac fibroblasts mediated the cardioprotective effects of ischemia post-conditioning. Furthermore, Hui et al. found that miR-423-3p was targeting the downstream effector Ras-related protein Rap-2c (RAP2C) in H9C2 cells [23]. The surface receptor of exosomes, besides the cargo, has the potential to act as a cardioprotective agent against cellular stress in dystrophin-deficient cardiomyopathy. The surface receptor of endogenous cardiomyocyte-secreted exosomes triggered the signaling pathway that included ERK1/2 and p38 MAPK, which were dysregulated in dystrophin-deficient cardiomyopathy [24]. These findings may be beneficial to patients with mutations in the DMD gene and patients with Duchenne muscular dystrophy, who might experience cardiomyopathy in the second or third decade of life [24, 25]. Table 1 shows the component of exosomes that can affect the cardiovascular system.

Table 1.

Effect of exosomes on the cardiovascular system.

No.	Component of Exosomes	Origin	Effect to Cardiovascular System	Mechanism
1	mtDNA	Plasma	Progression and worsening of CHF	Triggered an inflammatory response via the TLR9/NF-κB pathway
2	miR-217	Cardiomyocyte	Cardiac hypertrophy and dysfunction	Aggravate pressure overload-induced cardiac hypertrophy and dysfunction by suppressing PTEN expression
3	HSP90 and IL-6	Cardiomyocyte	Cardiac hypertrophy	AngII stimulates cardiac fibroblast to release exosome (with increased expression of HSP90 and IL-6) which upregulate Renin, Agt, AT1R and AT2R and downregulate ACE2 in cardiomyocyte.
4	miR-939-5p	Coronary serum	Induce Angiogenesis	The coronary serum exosomes from ischaemia patients have more miR-939-5p expression and induce angiogenesis
5	HSP70	Endothelial cell	Pro-atherosclerosis	A high level of extracellular HSP70 activates monocytes, leading to monocyte adhesion to endothelial cells
6	miR-155	Vascular smooth muscle cell (VSMC)	Promote atherosclerosis	VSMC-derived exosomes mediate the transfer or KLF5-induced miR-155 from VSMC to endothelial cells, which destroy tight junctions and integrity of endothelial barrier, and as a result the endothelial permeability increased and enhanced atherosclerosis progression
7	miR-10a	Endothelial cell	Suppress inflammation	Suppression of proinflammatory genes BTRC, MAP3K7, IRAK4
8	miR-423-3p	Cardiac fibroblast	Cardioprotective	miR-423-3p was targeting the downstream effector Ras-related protein Rap-2c (RAP2C) in H9C2 cells
9	Surface receptor	Cardiomyocyte	Cardioprotective	Triggered the signalling pathway that included ERK1/2 and p38 MAPK, which were dysregulated in dystrophin-deficient cardiomyopathy

mtDNA=mitochondrial DNA; miR=microRNA; HSP90=heat shock protein 90; IL-6=interleukin 6; TLR9/NF-κB=toll-like receptor 9/nuclear factor kappa-light-chain-enchancer of activated B cells; PTEN=phosphatase and tensin homolog; AngII=angiotensin II; Agt=angiotensiongen; AT1R=angiotensin II type 1 receptor; AT2R= angiotensin II type 2 receptor; ACE2=angiotensin converting enzyme 2; VSMC=vascular smooth muscle cells; KLF5=kruppel-like factor 5; BTRC=beta-transducin repeat containing E3 ubiquitin protein ligase; MAP3K7= Mitogen-Activated Protein Kinase Kinase Kinase 7; IRAK4=interleukin 1 receptor associated kinase 4; ERK1/2=extracellular signal-regulated kinase 1/2; MAPK=mitogen-activated protein kinase

5. EXOSOMES POTENTIAL AS DIAGNOSTIC MARKER IN CARDIOVASCULAR DISEASE

Exosomes are more stable than the cells, biocompatible, non-immunogenic, and resistant to cryo conservation without degrading, which makes them promising as a diagnostic marker in cardiovascular diseases [4]. miR-1 and miR-133a levels were elevated after the onset of chest pain while, on the other hand, there was no elevation in serum creatinine phosphokinase (CPK) or cardiac Troponin T (cTnT). miR-133a was superior because it was elevated within 2 hours after the onset of chest pain and was also elevated in patients with unstable angina pectoris (UAP) and Takotsubo cardiomyopathy [26]. In another study, the elevation of cardiac-specific miR-208a in plasma may be considered a biomarker for early detection of myocardial injury in humans. miR-208a was undetectable in non-AMI patients and detected in 90.9% AMI patients within 1 hour after the onset of symptoms. However, the percentage of AMI patients detected increased up to 100% within 4 hours after the onset of symptoms [27].

miR-1, miR-133a, miR-208b, and miR-499 were measured in AMI and normal patients, and all markers were found to be significantly higher in AMI patients. The area under the ROC curves of each miRNA was then measured. miR-1 0.8625 (95% CI, 0.7441-0.9088), miR-133a 0.9468 (95% CI, 0.9057-0.9879), miR-208b 0.8899 (95% CI, 0.8259-0.9540), and miR-499 0.8841 (95% CI, 0.8187-0.9495). These results demonstrate that the four miRNAs were sensitive and specific for AMI. However, the four miRNA was found to be inferior when compared with cTnT (0.9820 95% CI, 0.9289-0.9975) for diagnosing AMI (p>0.05) [28].

miR-1, miR-133a, miR-208b, and miR-499 were found to be consistently higher in AMI patients compared to normal patients. The miRNAs are specific and sensitive but still inferior compared to Troponin. These findings supported the possibility of exosomes’ cargo (miRNA) as a cardiovascular disease diagnostic marker, in this case, acute myocardial infarction. miRNA presence can be detected as early as 1 hour in 90.9% of AMI patients. The early presence of miRNA in AMI patients is beneficial when applied to clinical settings. As a comparison, high sensitivity cardiac Troponin (hs-cTn) after years of development and advances in technology can detect Troponin elevation related to myocardial infarction, usually within 1 hour from symptom onset [29]. In reality, not all hospitals have the hs-cTn examination, especially in developing countries that mostly rely on conventional assay in diagnosing myocardial infarction. The early detection of miRNA elevation which is comparable to hs-cTn may provide more time for referral or intervention procedure preparation or prohibit the patient from receiving overtreatment. Another advantage that miRNA possesses as a diagnostic marker is it can be detected using established examination (TaqMan qRT-PCR) with a relatively short time, approximately 80 minutes.

The disadvantages of the miRNAs lie in the lack of a large population study in determining the best cut-off point with the highest sensitivity and specificity for AMI patients. The study could also determine whether the cut-off point will also be suitable for a different population (gender, race, age, and comorbidities). Furthermore, several studies have identified the elevation of the miRNA in not only cardiac muscle but also skeletal muscle [30]. As a consequence, in the future, more studies are needed to determine the levels of the miRNA in conditions and diseases which affect skeletal muscle.

6. EXOSOMES POTENTIAL AS PROGNOSTIC MARKER IN CARDIOVASCULAR DISEASE

Cardio-enriched miRNAs (miR-1, miR-208, and miR-499-5p) were measured using plasma samples from patients suspected with acute coronary syndrome (ACS) to find its correlation with left ventricular systolic dysfunction, risk of heart failure, and risk of death. The increased cardio-enriched miRNAs were found to be correlated with LVEF, and strongly associated with increased risk of mortality or heart failure within 30 days [31]. Table 2 shows the component of exosomes that have the potential to be a diagnostic/prognostic marker.

Table 2.

Exosomes potential as diagnostic/prognostic marker in acute myocardial infarction (AMI) patients.

LVEF=left ventricular ejection fraction; miR=microRNA.

Further research should be focused on miRNAs which may act as both diagnostic and prognostic markers for AMI. One biomarker with dual function (diagnostic and prognostic), high sensitivity, and specificity will provide an efficient and cost-effective examination in clinical practice.

7. EXOSOMES POTENTIAL AS A THERAPEUTIC AGENT IN CARDIOVASCULAR DISEASE

Exosomes have emerged as a potential therapy for irreversible damage that occurs in the cardiovascular system. It has been considered to be the substitution of the whole-cell therapy or stem cell because it is stable, biocompatible, non-immunogenic, and non-tumorigenic [4]. Besides, exosomes are suitable to be loaded with therapeutic cargos [32]. These characteristics supported the potential of exosomes to be a therapeutic agent and there have been several studies that verify it.

Cardiac progenitor cells in the adult heart have been widely used as stem cells for cardiac regeneration and repair. However, cardiac progenitor cell-derived exosomes were known to play a significant part in the cardiac progenitor cells (CPC) functions [33]. Barile, L et al. identified that CPC secreted extracellular vesicles (EV) and the dominant component was exosomes. Several miR from the EV were identified, such as miR-210, miR-132, miR-146a, and miR-181. miR210 and miR-132 inhibited apoptosis in HL-1 cardiomyocytic cells, miR-210 downregulate ephrin A3 and PTP1, and miR-132 promoted tube formation in HUVEC. The researchers further examine the EV capability by injecting it to rats with an infarcted heart to assess the left ventricle and scarred tissue. The EV from CPC was found to be superior compared to EV from fibroblast because of the higher LVEF, less LV diameter increase, and systolic LV wall thickening. The superiority of EV from CPC was strengthened by the findings that the EV from CPC impacted the scarred areas to have significantly larger areas of viable tissue, TUNEL-positive apoptotic cardiomyocytes significantly decreased and blood vessel density significantly increased [34]. A study held by Xiao et al. showed that exosomes were secreted more in the oxidative stress model and from six apoptosis-related miRNAs, miR-21 was significantly upregulated. Furthermore, miR-21 played an important role in anti-apoptotic effect of H9C2 cells by decreasing PDCD4. These findings concluded that CPC derived exosomes prevent cardiomyocyte apoptosis through its miR-21 which targeted PDCD4 [35].

Mesenchymal stem cells (MSCs) were other stem cells that have been used to treat AMI because of their ability to differentiate into multiple cardiac cells. One of the MSCs that was currently used widely was Adipose-derived stem cells (ADSCs) because of the abundance, easily harvested by minimally invasive surgical techniques, and lack donor limitations [36, 37]. However, there was a potential risk of malignant transformation from the clinical application of MSCs [38]. On the other hand, exosomes were known to be secreted by the MSCs and have the potential to improve the therapy of AMI. The potential was proven to be right when Xiaojun et al. explained in their study about the impact of ADSCs-exosomes administration into the rats subjected to myocardial ischemia/reperfusion (I/R) injury and H9C2 cells exposed to hypoxia/reoxygenation (H/R). The ADSCs-exosomes significantly reduced I/R-induced myocardial infarction by upregulating Bcl-2, downregulating Bax, and inhibiting Caspase 3 activity in rat myocardium. Align with the findings, ADSCs-EXO also significantly reduced cell apoptosis in H/R-induced myocardial infarction by downregulating Bax and upregulating Bcl-2 and Cyclin D1. The mechanism underlying the antiapoptotic and prosurvival effects in H9c2 cells was related to the activation of Wnt/β- catenin signaling [38].

Qiancheng et al. through in vitro and in vivo models, investigate whether ADSC-derived exosomes enriched with miR-126 have a more protective effect on acute myocardial infarction or not. In the in vitro study, ADSC-derived exosomes enriched with miR-126 decrease H9c2 by reducing the expression of inflammation factor, thus reducing the myocardial cell injury. Furthermore, miR-126 enriched exosomes decrease fibrosis-related protein of H9c2 in hypoxic condition and significantly promotes the microvascular generation and migration using Matrigel and Transwell assay. In the in vivo model, the area of infarction of myocardial injury was significantly decreased by the administration of exosomes derived from ADSCs. The author concluded that miR-126-enhanced ADSC-derived exosomes protected the myocardial cells from apoptosis, inflammation, fibrosis, and increased angiogenesis [39]. The ability to protect myocardial cells by inhibiting inflammatory response was also found in ADSC-derived miR-93-5p, which also inhibits autophagy. The anti-inflammatory effect of miR-93-5p was caused by targeting Atg7 and Toll-like receptor 4 (TLR4) [40].

Exosomes from telocytes have the potential to prevent the worsening of the heart and improve cardiac function. Telocytes (TCs), a part of interstitial Cajal-like cells (ICJL), are cells that create a supportive interstitial network (physical and informational support) for cardiomyocyte progenitors and also participate in neo-angiogenesis during the late stage of myocardial infarction [41, 42]. In the in vitro study conducted by Jie et al., to determine the effect of exosomes secreted by TCs, found that endothelial cells cultured in telocytes showed increase proliferation, migration, and formation of capillary-like structures. The finding was then confirmed with the in vivo study by transferring the exosomes into MI-induced rats. The result showed that cardiac fibrosis decreased, angiogenesis increased and cardiac function improved [43]. The summary of exosomes’ potential as a therapeutic agent in cardiovascular disease can be seen in Fig. (2).

Fig. (2).

The summary of exosomes’ potential as a therapeutic agent in cardiovascular diseases. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

CONCLUSION

Exosomes affected the cardiovascular system positively or negatively depends on the origin of the exosomes and the component of the exosomes involved. MicroRNA derived-exosomes have the potential to become a diagnostic marker (miR-1, miR-133a, miR-208b, and miR-499) in AMI patients and prognostic marker (miR-1, miR-208, miR-499-5p) in cardiovascular patients. The normal value of exosomes and the component of exosomes needs to be standardized according to the conditions affecting the patients and the method of isolation used to be a reliable biomarker. CPC-derived exosomes, ADSCs-derived exosomes, and telocyte-derived exosomes have been proven to be dose-dependent and beneficial as therapy in myocardial infarction models. Exosomes have the potential to become a diagnostic marker, prognostic marker, and therapy in the cardiovascular system but further clinical trials are needed to confirm the findings.

LIST OF ABBREVIATIONS

ADSC

Adipose Derived Mesenchymal Stem Cell

ACE2

Angiotensin Converting Enzyme 2

ACS

Acute Coronary Syndrome

Agt

Angiotensin

AMI

Acute Myocardial Infarction

AngII

Angiotensin II

AT1R

Angiotensin Type 1 Receptor

AT2R

Angiotensin Type 2 Receptor

Atg7

Autophagy Related 7

Bax

Bcl-2-associated X protein

Bcl-2

B-cell lymphoma 2

BTRC

Beta-Transducin Repeat Containing

CHF

Chronic Heart Failure

CPC

Cardiac Progenitor Cell

cTnT

cardiac Troponin T

EXO

Exosomes

ESCRT

Endosomal Sorting Complexes Required for Transport

EV

Extracellular Vesicles

hnRNP

heterogeneous nuclear Ribonucleoprotein

HSP

Heat Shock Protein

hs-cTn

high sensitivity cardiac Troponin

HUVEC

Human Umbilical Vein Endothelial Cells

ICJL

Interstitial Cajal-like Cells

IL-

Interleukin-

iNOS

inducible Nitric Oxide Synthase

IRI

Ischemia-Reperfusion Injury

IRAK4

Interleukin-1 Receptor-Associated Kinase 4

LV

Left Ventricle

LVEF

Left Ventricular Ejection Fraction

MAP3K7

Mitogen-Activated Protein Kinase 7

MEX3C

Mex-3 RNA Binding Family Member C

miRNA/miR-

micro Ribonucleic Acid-

miRISC

miRNA Induced Silencing Complex

MSCs

Mesenchymal Stem Cells

mtDNA

mitochondrial Deoxyribonucleic Acid

MVB

Multivesicular Bodies

MVE

Multivesicular Endosomes

NF-κB

Nuclear Factor-kappaB

PDCD4

Programmed Cell Death 4

PTP1

Protein Tyrosine Phosphatase 1

RAP2C

Ras-related Protein Rap-2c

RBP

RNA Binding Protein

TCs

Telocytes

TLR4

Toll Like Receptor 4

TLR9

Toll Like Receptor 9

TUNEL

TdT-mediated dUTP Nick-End Labeling

YBX-1

Y-Box Binding Protein 1

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.