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Exosome-Regulated Oxidative Stress Responses: Comparison
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Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Ken Takahashi.

A thrombus in a coronary artery causes ischemia, which eventually leads to myocardial infarction (MI) if not removed. However, removal generates reactive oxygen species (ROS), which causes ischemia–reperfusion (I/R) injury that damages the tissue and exacerbates the resulting MI. The mechanism of I/R injury is currently extensively understood. However, supplementation of exogenous antioxidants is ineffective against oxidative stress (OS). Enhancing the ability of endogenous antioxidants may be a more effective way to treat OS, and exosomes may play a role as targeted carriers. Exosomes are nanosized vesicles wrapped in biofilms which contain various complex RNAs and proteins. They are important intermediate carriers of intercellular communication and material exchange.

  • exosome
  • oxidative stress
  • exosome therapy
  • myocardial infarction
  • coronary heart disease
  • reactive oxygen radicals

1. Introduction

Cardiovascular disease (CVD) has been the leading cause of mortality in recent years, and its incidence and mortality are closely related to coronary heart disease (CHD). CHD could cause a huge economic burden to regional or national medical systems [1,2][1][2]. CHD is, in fact, an inflammatory disease. Oxidative stress (OS) plays an important role in the development of coronary artery disease, and it is mainly caused by an imbalance between reactive oxygen species (ROS) production and endogenous antioxidant defense system. At low levels, ROS causes subtle changes in intracellular pathways, such as redox signal transduction, but at higher levels it causes cell dysfunction and damage [3,4,5][3][4][5]. In the current research on exogenous anti-OS, the effects of OS damage were mot significantly reduced [6,7][6][7]. At present, strategies for the clinical treatment and prevention of atherosclerotic CVD still focus on the pharmacotherapy of arachidonic acid metabolism and antiplatelet aggregation (platelet P2Y12 inhibitors), as well as the treatment of related risk factors, such as high blood pressure, excessive lipids, and high blood sugar [8,9,10,11,12,13][8][9][10][11][12][13].

Exosomes are small vesicles [14,15,16][14][15][16] that contain complex RNAs and proteins which are found in natural body fluids, including blood, saliva, urine, cerebrospinal fluid, and milk [17,18][17][18]. Discovered in 1946, exosomes were first considered as “clotting factors” [19] that improved coagulation. After 20 years, electron microscopy revealed that platelet products contain vesicles measuring 20–50 nm [20]. Until 1987, Johnstone named these vesicles as “exosomes” [21]. Exosomes can be used as carriers for intercellular communication and can regulate protein expression in receptor cells by RNA transfer [22]. Intercellular communication is necessary in maintaining tissue/organ integrity/homeostasis and inducing adaptive changes to exogenous stimuli. In response to environmental damage and pathological conditions, many cell types release various exosomes of different quality and quantity into the circulation [23,24][23][24]. During OS, the exosomes released by cells can mediate signal transduction, change the defense mechanism of receptor cells, and enhance their resistance to OS [23]. In recent years, considerable attention was paid to the important role of exosomes in CVDs, such as ischemic heart disease [25,26,27,28,29][25][26][27][28][29].

Exosomes are released from damaged or diseased hearts, playing an important role in disease progression [30,31,32,33][30][31][32][33]. Considering the related experiments and clinical cell therapy studies, the important roles of exosomes in myocardial injury, repair, and regeneration are being increasingly recognized. According to some studies, the Framingham risk score used to predict CVD risk correlates with circulating exosomes [34,35][34][35]. Therefore, exosomes in the circulatory system are potential biomarkers of CVD. The selective packaging of miRNAs in exosomes and their functional transfer through specific signaling molecules are also important for disease treatment [36,37][36][37]. In addition, exosomes help detect the endogenous processes of myocardial recovery, regeneration, and protection [38]. They reflect the real-time microenvironment of the lesion, indicating that they are excellent biomarkers in clinical diagnosis. Exosomes are extremely useful because they can determine the pathophysiology of heart disease noninvasively.

In ischemic myocardium, especially after reperfusion, numerous ROS are produced [39,40][39][40]. ROS directly damage tissues, inducing cell death. In transgenic mice, infarct size was found to be significantly reduced when the antioxidant protein superoxide dismutase (SOD) was overexpressed [41,42][41][42]. Increasing the level of endogenous antioxidants can prevent reperfusion injury [43,44][43][44]. Exosomes can provide precise treatment through miRNAs by selecting the corresponding target cells and manipulating the corresponding components; thus, exosomes are a powerful tool for individualized therapy and gene therapy [45,46,47][45][46][47]. Therefore, the upregulation of endogenous antioxidants through exosomes seems to have good prospects.

2. Exosome-Regulated OS Responses after Myocardial Ischemia

Although initially identified as cell debris, exosomes have many functions regulated by multiple signaling pathways. Exosomes are widely involved in the regulation of OS [48,49][48][49] and pathophysiological regulation of various cells; cellular pathophysiological processes include signal transduction, antigen presentation, and immune response [50,51][50][51]. Many of the previously conducted studies attempted to provide a detailed summary of the biogenesis of exosomes [52,53,54][52][53][54]. Figure 1 provides an illustration of exosome secretion under OS.

Ijms 22 01729 g001 550
Figure 1.

Exosome secretion under OS. Parent cells secrete exosomes containing antioxidant molecules that lead to cardioprotection (

A

) and/or microRNAs (miRs) that lead to inhibition of apoptosis (

B

). MSCs secrete SOD1, GPX1, and miR-19a without OS or hypoxia and protect cardiomyocytes exposed to OS. MSC: mesenchymal stem cells; CPC: cardiac progenitor cell; SOD1: superoxide dismutase 1; GPX1: glutathione peroxidase 1; GST: glutathione S-transferase; TAGLN2: transgelin 2; DAPK2: death-associated protein kinase 2; ISCU: iron–sulfur cluster assembly enzyme; PDCD4: programmed cell death 4.

In recent years, many studies concerning CVD highlighted that exosomes not only transport proteins, RNA, DNA, and other molecules under physiological conditions but also participate in pathological conditions such as ischemia–reperfusion (I/R) injury, atherosclerosis, and cardiac remodeling [55,56,57,58,59,60,61][55][56][57][58][59][60][61]. They can modify gene expression and protein synthesis by inhibiting protein synthesis or initiating mRNA degradation to perform their functions at the post-transcriptional level. Moreover, circulating exosomes are considered as new biomarkers of disease performance and progression [57,62,63][57][62][63].

Under pathological conditions, the exosomes released during OS carry antioxidant molecules, such as superoxide dismutase 1 (SOD1) and glutathione S-transferase (GST) [62[62][63],63], and defense molecules, such as glutathione peroxidase 1 (GPX1) [64], which can be absorbed by neighboring cells to enrich their cellular defense mechanisms; thus, these cells are already protected from OS induced by adverse environmental conditions. Therefore, exosomes can potentially transfer defense molecules from one cell to another [65]. For example, in vitro, serum exosomes from healthy human volunteers attenuated H2O2-induced H9c2 cell apoptosis via ERK1/2 signaling pathway activation [66]. Moreover, cardiomyocytes (CMs) secrete miR-30a–rich exosomes after hypoxia stimulation [67]. When the release of miR-30a from exosomes is inhibited, autophagy and OS response in CMs may be maintained after hypoxia [68].

Furthermore, rapid ROS increase and OS occurrence are related to antioxidant depletion. Supplementation of related exogenous antioxidants, such as vitamin E and folic acid, might achieve good effects against OS [69,70][69][70]. However, a recent meta-analysis of randomized controlled trials involving 294,478 participants indicated that supplementation of exogenous vitamins and antioxidants was not associated with a reduction in the risk of major CVDs [71]. Interestingly, supplementation with N-acetylcysteine to increase endogenous antioxidants (e.g., glutathione (GSH)) can achieve good antioxidant capacity. After being absorbed by cells, N-acetylcysteine is transformed into cysteine. When the cysteine level increases, the synthesis rate of GSH also increases. More importantly, N-acetylcysteine supplementation not only improves the prognosis of patients but also produces no adverse side effects [72,73,74,75][72][73][74][75]. Increasing the ratio of GSH/oxidized GSH (GSSG) in patients with heart failure and acute myocardial infarction (MI) can reduce OS and improve the MI area and cardiac function [72,73,74,75][72][73][74][75]. This finding is also beneficial for the treatment of exosomes, considering that endogenous antioxidants, such as catalase, can be delivered directly through exosomes [76]. Catalase is the main enzyme that regulates H2O2 metabolism. The level of catalase gradually decreases over time after MI [77]. Its overexpression can reduce myocardial I/R injury [78]. After reformation and reshaping of exosomes by sonication and extrusion procedures, catalase could be loaded into exosomes, with a loading capacity of 20–26% [79]. In addition, catalase exosomes can be obtained by modifying parent cells (monocytes/macrophages) and then isolating from the conditioned medium [80].

As natural drug delivery nanoparticles, exosomes have the advantages of cell-based drug delivery and nanoscale size, which aid in achieving effective drug delivery. Exosomes are also lipid vesicles and ideal carriers [81]. In recent years, the application of exosomes as a biomaterial for drug delivery has improved rapidly. At present, treatment with autologous exosomes can help obtain long-term and stable activation of immune effectors [82]. Furthermore, certain drugs can modify exosomes to form carriers with different properties. In mice, the introduction of polyethylene glycol to the exosome surface significantly increased the circulation time of exosomes [83]. However, systemic delivery of exosomes appears to accumulate in the spleen and liver [84,85,86][84][85][86]. To solve this issue, we need to modify the exosomes to increase their targeting to specific tissues or cells. Cells that produce exosomes should be engineered to drive the expression of targeting moieties fused with exosomal membrane proteins. For example, Alvarez-Erviti et al. [87] modified dendritic cells to express Lamp2b, an exosomal membrane protein fused to neuron-specific rabies viral glycoprotein (RVG) peptide, to obtain exosomal targeting. In addition, Wiklander et al. [88] found that compared with unmodified exosomes, RVG-targeted exosomes greatly accumulate in the brain after systemic administration. At the same time, the ability of exosomes to target hypoxic cells in vivo can be enhanced by combining exosomes with hypoxia-targeting peptides or antibodies through bioengineering technology [89,90][89][90]. Moreover, exosomes released by different cells, such as immune cells, may be more effective in targeting hypoxic tissue in vivo [91]. An alternative strategy for the noninvasive targeting of magnetic drugs (i.e., enhancing drug delivery to selected tissues by applying a magnetic field gradient) was also proposed decades ago [92,93][92][93]. In this strategy, the therapeutic agent and iron oxide nanoparticles together with macrophages are incubated, leading to the production of exosomes loaded with both the therapeutic and magnetic nanoparticles. However, this method may have the disadvantages of toxicity and difficulty in targeting deep tissues. Moreover, exosomes can be used for different ways, such as intraperitoneal injection, subcutaneous injection, and nasal administration. Different administration routes may help improve the therapeutic effect [94]. For example, the intranasal administration of catalase-loaded exosomes in a mouse model of Parkinson’s disease resulted in the increased accumulation of exosomes in brain tissue after four hours [76].

Exosomes as carriers can prevent internal molecular degradation and target special tissues, thereby improving bioavailability and reducing side effects. Moreover, exosomes can serve as carriers for drug delivery and have the potential to easily manipulate the expression of RNA and proteins [87]. Exosomes naturally occur and possess adhesion proteins, which can bind to target cells and remain in target tissues during transplantation [95]. In addition, exosomes have long-term preservation and no degradation because of the existence of resistant membranes. The membrane of exosomes may pass through the blood–brain barrier [96].

Exosomes have great advantages as carriers; however, “nonvesicles,” which are distinct particles that have low electron density without restrictive membranes, are present in exosome preparation [97]. Nonetheless, the appearance of artificial nanovesicles (exosome-mimetic nanovesicles) [91,98][91][98] may be helpful in solving this issue.

3. Several Possible Exosomal miRNA Loads

Exosomes contain various molecules, including proteins, lipids, DNA, mRNA, and miRNA, and relevant data can be acquired from the ExoCarta database [99]. Considering the various regulatory roles of miRNA in gene expression, more attention was paid to miRNA. The proportion of miRNA in exosomes is higher than that in their parent cells [100], and miRNA can be transferred between cells through exosomes [22,36][22][36]. Meanwhile, miRNAs in exosomes are protected by vesicles and can be stably maintained in circulation; eventually, they are transferred to target cells to inhibit the expression of some genes [101,102][101][102]. For example, the knockdown of beta-secretase 1 (BACE1) mRNA and protein was detected in mouse brains after tail vein injection of siRNA-containing exosomes [87]. Therefore, miRNA seems to have a good potential as a content in exosomes.

4. Advantages of Exosome Therapy in CHD Compared with Those of Stem-Cell Therapy

Over the years, various strategies were tried to find a more effective treatment after CVD occurrence. Currently, stem-cell therapy is an attractive method for CHD prevention and treatment [143,144,145][103][104][105]. In 1993, Koh et al. [146][106] proved that skeletal muscle myoblasts can be stably transplanted into CMs, demonstrating long-term survival, proliferation, and differentiation. Recently, research focus shifted to bone marrow-derived MSCs [147][107], and the relevant experiments achieved favorable results [148,149,150][108][109][110]. Previously, differentiation characteristics were the main mechanism for cell transplantation to exert therapeutic effects, however, stem cells did not necessarily differentiate into CMs or endothelial cells after transplantation into ischemic myocardium, but the antiapoptotic, antioxidant stress, and anti-inflammatory effects were mediated by exosomes, thereby improving cardiac function after ischemia [151][111]. Furthermore, stem-cell transplantation can lead to arrhythmia [152,153,154,155,156,157,158][112][113][114][115][116][117][118].

The secretory properties of cell transplantation represent an important scientific issue in CHD. Interestingly, exosomes produced during myocardial ischemia can mediate the preventive and therapeutic effects of cell transplantation [159][119]. Exosomes do have a protective effect on the cardiovascular system [26[26][120],160], which was first reported more than 10 years ago [161][121]. In porcine and mouse models of myocardial I/R injury, 100–200 nm macromolecular complexes secreted by stem cells protected cells under OS. In the subsequent biophysical studies, the biologically active component was characterized as an exosome. More direct evidence suggested that adult stem cells repair heart tissue by releasing paracrine and autocrine factors [162][122]. For instance, in the isolated Langendorff I/R injury model, purified exosomes derived from MSCs reduced MI in mice [62]. In further experiments, exosome therapy restored the energy consumption and OS levels of the mouse heart within 30 min after I/R and activated cardioprotective PI3K/Akt signaling [163][123]. Results of a meta-analysis confirmed these cardioprotective effects of MSC-derived exosomes in myocardial injury [164][124]. I/R results in consumption of intracellular ATP to a large extent, and exosomes from adipose-derived stem cells (ADSCs) were observed to supplement intracellular ATP, NADH, phosphorylated AKT, and phosphorylated GSK-3β levels, while reducing phosphorylated c-JNK and recovering cell bioenergy [165][125]. The exosomes from ADSCs also increase IL-6 expression and phosphorylate STAT3, which in turn activates the classical signaling pathway and accelerates recovery from injury and angiogenesis after I/R [166][126]. The effects of exosomes derived from stem cells due to reduction of myocardial OS damage are summarized in Table 1.

Table 1. Effect of exosomes derived from stem cells on the reduction of myocardial oxidative stress (OS) damage. ADSC: adipose-derived stem cell; CPC: cardiac progenitor cell; MSC: mesenchymal stem cell; ATG7: autophagy-related 7; TLR4: Toll-like receptor 4; PDCD4: programmed cell death 4.

Origin of Exosome

Mechanistic Detail of OS Damage Reduction

References

ADSC

promotes neovascularization and alleviates inflammation and apoptosis

[165]

[125]

upregulated miR-93-5p suppresses autophagy and inflammatory cytokine expression by targeting ATG7 and TLR4

[174]

[127]

CPC

upregulated miR-21 inhibits apoptosis by targeting PDCD4

[175]

[128]

inhibits caspase 3/7 activity

[173]

[129]

activates ERK1/2 pathway and inhibits apoptosis

[66]

MSC

increases ATP level and activates PI3K/Akt pathway

[163]

[123]

activates Akt/Sfrp2 pathway

[176]

[130]

upregulated miR-19a activates Akt/ERK pathway

[109]

[131]

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