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. 2022 Nov 5;130(1):29–38. doi: 10.1016/j.bja.2022.08.040

Plasma exosomes generated by ischaemic preconditioning are cardioprotective in a rat heart failure model

Zhaofei Luo 1,2,†, Xudong Hu 1,2,†, Chao Wu 1,2, Jinzhong Chan 1,2, Zhong Liu 1,2, Chengxiao Guo 1,2, Rui Zhu 1,2, Li Zhang 3, Ye Zhang 1,2, Shiyun Jin 1,2,∗, Shufang He 1,2,∗
PMCID: PMC9875906  PMID: 36347723

Abstract

Background

Exosomes released into the plasma after brief cardiac ischaemia mediate subsequent cardioprotection. Whether donor exosomes can provide cardioprotection to recipients with chronic heart failure, which confers the highest perioperative risk, is unknown. We examined whether ischaemic preconditioning (IPC)-induced plasma exosomes exerted cardioprotection after their transfer from normal donors to post-infarcted failing hearts.

Methods

Plasma exosomes were obtained from adult rats after IPC or sham. An exosome inhibitor GW4869 was administrated before IPC in an in vivo model of ischaemia/reperfusion (I/R) injury in normal rats. The IPC exosomes or control exosomes from normal donor rats were perfused to the normal or post-infarcted failing rat hearts before ischaemia in Langendorff perfusion experiments. Infarct size, cardiac enzymes, cardiac function, and pro-survival kinases were quantified.

Results

The IPC stimulus increased the release of exosomes, whereas GW4869 inhibited the rise of plasma exosomes. Pre-treatment with GW4869 reversed IPC-mediated cardioprotection against in vivo I/R injury. In the Langendorff perfusion experiments, IPC exosomes from normal donor rats reduced mean infarct size from 41.05 (1.87)% to 31.43 (1.81)% and decreased lactate dehydrogenase activity in the post-infarcted failing rat hearts. IPC exosomes but not control exosomes activated pro-survival kinases in the heart tissues.

Conclusions

Ischaemic preconditioning-induced exosomes from normal rats can restore cardioprotection in heart failure after myocardial infarction, which is associated with activation of pro-survival protein kinases. These results suggest a potential perioperative therapeutic role for ischaemic preconditioning-induced exosomes.

Keywords: cardioprotection, exosome, heart failure, ischaemic preconditioning, pro-survival kinases

Editor's key points.

  • •

    Cardioprotection for patients with heart failure may reduce their perioperative risk.

  • •

    Exosomes released after cardiac ischaemia provide cardioprotection.

  • •

    The authors examined whether transferring exosomes derived after cardiac ischaemia in one set of rats were protective in another set of rats with heart failure.

  • •

    Transferred exosomes reduced cardiac damage in recipient rats by activating pro-survival kinases in the heart.

  • •

    This experimental approach provides a potential therapy for reducing perioperative myocardial injury.

Myocardial ischaemia/reperfusion (I/R) injury is associated with poor clinical outcomes after major surgery.1,2 Patients with heart failure undergoing major surgery sustain more complications and may be more vulnerable to I/R injury.2, 3, 4, 5 Minimising cardiac I/R injury is likely to improve outcomes after major surgery but particularly so in patients with heart failure.6,7

Ischaemic preconditioning (IPC) of the heart occurs as a result of several brief episodes of repeated I/R before subsequent prolonged ischaemia.1 Although IPC appears to be a powerful cardioprotective intervention, clinical translation has been largely disappointing.8 In particular, the cardioprotective effect of IPC is diminished in chronic heart failure, perhaps as a result of impaired pro-survival kinase signalling through extracellular signal regulated kinases (ERKs) and protein kinase B (Akt).3,4,9 However, pharmacological approaches that mimic IPC may reduce myocardial I/R injury in models of heart failure.9, 10, 11, 12 These data suggest that identifying the humoral factors involved may enable the transfer of IPC-mediated cardioprotection from normal state to the pathologic heart.

Exosomes are lipid bimolecular membrane nanoparticles with 30–100 nm in diameter that are generated and secreted by almost all cell types. Exosomes contain proteins, mRNAs, and microRNAs that regulate various physiological and pathological processes through cellular communication.13,14 Although exosomes play a role in preconditioning-induced cardioprotection,15, 16, 17 it remains unclear whether donor exosomes generated by IPC can reduce I/R injury in recipients with heart failure. We hypothesised that the delivery of IPC-induced exosomes could provide therapeutic benefits to patients with heart failure in need of cardioprotective strategies during the perioperative period. To address this question, we generated exosomes by inducing IPC in normal rats and transferred these exosomes to rats with post-infarction heart failure.

Methods

Study design

This experimental laboratory study was performed in accordance with the guidelines for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee of Anhui Medical University. Adult male Sprague-Dawley rats (200–230 g) were used to establish post-infarction heart failure as described11 (Supplementary data).

Extraction, purification, and verification of exosomes

Adult male rats used for exosome generation were randomly divided into four groups (n=6/group): control, IPC, exosome inhibitor GW4869+IPC (GW+IPC), and GW4869 alone (GW) group. Intraperitoneal injection of GW4869 at the dose of 2 mg kg−1 was chosen from previous studies.18, 19, 20 Exosomes were extracted and purified from plasma using the ExoQuick™ kit (SBI, Palo Alto, CA, USA), according to the manufacturer's instructions. Biological and structural characteristics of exosomes were evaluated by transmission electron microscopy (TEM), dynamic light scattering (DLS), and Western immunoblot, respectively.

Myocardial ischaemia/reperfusion injury in vivo

To investigate the role of exosomes in IPC-induced cardioprotection, adult male rats were randomly divided into five groups (n=6 in each group): sham, I/R, IPC, GW+IPC, and GW+I/R groups. Myocardial I/R injury was established by a 30-min ligation of the left anterior descending coronary artery with 6–0 silk suture, followed by 120 min of reperfusion. The extent of cardiac injury was determined by measuring the infarct size using 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. Cardiac troponin I and creatine phosphokinase-MB were measured by ELISA method. ECG of the experimental animals was applied during the entire procedure using PowerLab System (ADInstruments, Bella Vista, Australia) to record haemodynamic parameters and incidence of ventricular arrhythmia.

Langendorff-based ex vivo ischaemia/reperfusion injury and exosome administration

Langendorff-perfused isolated rat hearts were subjected to global I/R injury, as described previously with minor modifications.9,11 These hearts were randomly divided into four groups (n=6 in each group), respectively: sham, I/R, C-Exo+I/R, and I-Exo+I/R group. The isolated hearts were perfused with the modified Krebs–Henseleit (KH) solution (118.5 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO4, 1.2 mM KH2PO4, 1.25 mM CaCl2, 25.0 mM NaHCO3, and 11.0 mM glucose; pH 7.35–7.45) at constant pressure of 100 cm H2O.10 All rat hearts were stabilised for 15 min and subjected to 30 min no-flow global ischaemia followed by 120 min reperfusion except that the hearts from the sham group were perfused with KH solution continuously until the end of the experiment. The isolated hearts from the I-Exo+I/R or C-Exo+I/R group were perfused with IPC exosomes (I-Exo) or control exosomes (C-Exo) at a concentration of 40 μg ml−1 for 15 min before global ischaemia, respectively. Cardiac injury was determined by infarct size and lactate dehydrogenase (LDH) activity of coronary effluents. The haemodynamic parameters, including left ventricular developed pressure, HR, and coronary flow, were continuously monitored and recorded using the PowerLab System.

Statistical analysis

Data are presented as mean (standard error of the mean). Haemodynamic parameters and LDH values were analysed using repeated measures analysis of variance (anova) with post hoc Tukey–Kramer testing for multiple comparisons. The unpaired two-tailed t-test was used for comparison between two groups, and one-way anova followed by a Tukey's test was used for multiple comparisons. P<0.05 was considered significant (GraphPad Prism 8.0, GraphPad Software, San Diego, CA, USA). The sample size in each group was determined by a priori power calculation based on our previous studies (G∗Power, Heinrich-Heine-Universität Düsseldorf, version 3.1.7).10,11

Results

Experimental model

In this study, 206 rats were used, with 55/71 surviving after surgery to establish the model of post-infarction heart failure (Supplementary Fig. S1). The Supplementary material details the reasons for exclusion from the final experiments.

Ischaemic preconditioning increases plasma exosome content in normal rats

We first established that exosomes could be extracted from the plasma of normal rats undergoing IPC (Fig. 1a). TEM verified that isolated exosomes showed typical ‘cup-shaped’ double-layer morphology, with uniform size distribution of ∼100 nm diameter (Fig. 1b). DLS showed that exosomes from all groups displayed a single peak in volume distribution profile with the diameter range of 10–100 nm (Fig. 1c). Although similar morphological characteristics of exosomes were observed in all groups, IPC increased plasma exosome content compared with controls. Pre-treatment with the exosome inhibitor GW486918, 19, 20 reduced IPC-induced elevation of exosomes without changing the baseline level of exosome content (Fig. 1d). Immunoblotting for CD63 and HSP70 proteins, specific biomarkers for extracted exosomes21, 22, showed similar results (Fig. 1e and f), with GW4859 reducing IPC-induced exosomes in plasma.

Fig 1.

Fig 1

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IPC promotes the release of plasma exosomes in rats. (a) Schematic diagram illustrating the extraction and verification of exosome derived from normal rat plasma. (b) Representative transmission electron micrographs of exosomes extracted from rats in each group. Scale bar represents 100 nm. (c) Dynamic light scattering analysis of exosomes showing size distribution by volume. (d) Bar graph shows the exosome content in normal rat plasma at the end of ischaemic preconditioning (n=6 rats per group). (e) Representative bands of the exosomal protein CD63 and HSP70. (f) The relative levels of exosomal protein CD63 and HSP70 (n=4 per group). Data are presented as mean [standard error of the mean]. BCA, bicinchoninic acid assay; GW, GW4869; IPC, ischaemic preconditioning.

GW4869 blocks the cardioprotective effects of exosomes induced by ischaemic preconditioning in vivo in normal rats

GW4869 was administrated before IPC and I/R (Fig. 2a). IPC reduced infarct size, arrhythmia score, and biochemical markers of I/R injury (Fig. 2b–e). GW4869 increased the infarct size (Fig. 2b) and prevented the beneficial effects of IPC on the arrhythmia score and biochemical markers of I/R injury (Fig. 2c–e). GW4869 alone did not alter the extent of myocardial I/R injury(Fig. 2b-e). Morphometric and haemodynamic parameters were not different among groups, other than the sham group (Supplementary Table 1 and 2).

Fig 2.

Fig 2

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Effects of GW4869 on IPC-induced cardioprotection against in vivo I/R injury in normal rats. (a) Schematic diagram illustrating the in vivo experimental protocols. (b) Representative images of heart sections stained by triphenyltetrazolium chloride (TTC) and infarct size (IS) expressed as a percentage of area at risk (AAR) for each experimental group. The non-ischaemic area stained blue and AAR was brick red, whilst IS was white (n=6 rats per group). (c–d) The activities of cTnI and CK-MB in each group (n=6 rats per group). (e) Arrhythmia score was analysed in each group (n=6 rats per group). Data are presented as mean [standard error of the mean]. CK-MB, creatine phosphokinase-MB; cTnI, cardiac troponin I; GW, GW4869; IPC, ischaemic preconditioning; I/R, ischaemia/reperfusion.

Ischaemic preconditioning exosomes protect normal and failing rat hearts against ischaemia/reperfusion injury ex vivo

Because IPC has failed to be cardioprotective in heart failure and cardiac hypertrophy,4,9,23 we next tested whether IPC exosomes from normal rats could protect the isolated failing rat heart against I/R injury. Using the Langendorff perfusion model (Fig. 3a), we found that 40 μg ml−1 IPC exosomes were most cardioprotective against I/R injury in normal hearts (Fig. 3b and d; Supplementary Fig. S2). IPC exosomes obtained from normal rats also protected the isolated and post-infarcted failing hearts against I/R injury (Fig. 3c and e). In contrast, the perfusion of control exosomes from non-IPC rats failed to produce cardioprotection after I/R injury in both normal and post-infarcted failing isolated hearts (Fig. 3b-e). Morphometric and haemodynamic parameters were not different among groups, other than the sham group (Supplementary Table 3 and 4).

Fig 3.

Fig 3

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IPC-derived exosomes exert cardioprotection against I/R injury in both normal and failing isolated rat hearts. (a) Schematic diagram illustrating the Langendorff experimental protocols. (b) Representative images of heart sections stained by triphenyltetrazolium chloride (TTC), and the infarct size (IS) is expressed as a percentage of area at risk (AAR) in normal isolated hearts. (c) Representative images of the failing heart sections stained by TTC, and the IS is expressed as a percentage of AAR in failing isolated heart (n=6). (d–e) The activity of lactate dehydrogenase (LDH) in coronary effluents was measured at baseline, 5 min, and 10 min after reperfusion (P5 and P10) in normal and failing isolated hearts. Data are presented as mean [standard error of the mean]. ∗P<0.05; ∗∗P<0.01; ∗∗∗P<0.001; ∗∗∗∗P<0.0001. C-Exo, control exosome; I-Exo, IPC exosome; IPC, ischaemic preconditioning; I/R, ischaemia/reperfusion; ns, not significant.

Ischaemic preconditioning exosomes activate the kinases ERK1/2 and Akt in the isolated normal and failing rat hearts

Pre-incubation with IPC exosomes enhanced the phosphorylation levels of pro-survival ERK1/2 kinases1,24 in both normal and failing hearts after I/R injury (Fig. 4a and b). IPC-derived exosomes also up-regulated Akt phosphorylation in heart failure and normal hearts after I/R injury (Fig. 4c and d). Increased ERK1/2 and Akt phosphorylation were not observed after pre-incubation with exosomes from rats not subjected to IPC (in both normal and failing rat hearts).

Fig 4.

Fig 4

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Both ERK1/2 and Akt are activated by IPC exosomes in normal and failing isolated rat hearts. (a–b) Representative Western blot images and the relative expression levels of p-ERK1/2 normalised to the total ERK1/2 and GAPDH in (a) normal and (b) failing rat hearts (n=4 rats per group). (c–d) Representative Western blot images and the relative expression levels of p-Akt normalised to the total Akt and GAPDH in (c) normal and (d) failing rat hearts (n=4 rats per group). Data are presented as mean [standard error of the mean]. Akt, protein kinase B; C-Exo, control exosomes; ERK, extracellular signal-regulated kinase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; I-Exo, IPC exosomes; I/R, ischaemia/reperfusion; Sham, sham operation.

Discussion

Our data suggest that the release of plasma exosomes from normal donor rats mediated the cardioprotective effects induced by IPC. Such IPC exosomes carried, transferred, and exerted the therapeutic efficacy of cardioprotection to post-infarct failing hearts. These exosomes mediate IPC cardioprotection through the activation of the pro-survival ERK and Akt (Fig. 5).

Fig 5.

Fig 5

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Schematic shows Ischaemic preconditioning-derived exosomes from normal rats protect post-infarcted failing heart against ex vivo I/R injury by activating pro-survival kinases. Akt, protein kinase B; ERK, extracellular signal-regulated kinase; IPC, ischaemic preconditioning; I/R, ischaemia/reperfusion; P, phosphorylation.

Exosomes play an important role in intercellular communication by delivering various cargos, including protein, lipids, microRNA, and other bioactive molecules.13,14 Ischaemic or hypoxic preconditioning promotes exosome release into plasma, coronary perfusates, or culture medium.25, 26, 27 Administration of exosomes induced by IPC can ameliorate cardiomyocyte apoptosis, reduce infarct size, and improve cardiac function in recipient hearts.15,28 In the present study, we showed that IPC stimulus on the intact rat hearts promoted the release of exosomes into plasma. However, when IPC-induced elevation of exosomes was inhibited by the exosome inhibitor GW4869, the protective effects of IPC in reducing infarct size, arrhythmia score, and the activities of cardiac enzymes were largely blunted. Similar results were demonstrated in a previous study that IPC-treated hearts failed to confer cardioprotection to recipient hearts when the exosomes were depleted.16 Of note, neither IPC nor GW4869 treatment affected the size distribution profile and morphology of exosomes. These data suggest that IPC exerts cardioprotection against I/R injury, at least in part, by increasing the release of exosomes.

Ischaemic preconditioning is well known as an innate protective mechanism. However, several clinical studies demonstrated that preconditioning did not improve clinical outcomes in patients undergoing elective on-pump coronary artery bypass graft with cardiac surgery.29,30 The cardioprotective effect induced by IPC appears to be diminished in the presence of many common pathological conditions.23 Moreover, IPC also lost its cardioprotection in the setting of post-infarcted heart failure because of the inactivation of pro-survival kinases.9,31 These observations suggest that IPC cardioprotection cannot be established effectively in humans and animals with comorbidities, including heart failure. In this study, we tested the idea if those IPC exosomes from normal donors can protect failing heart, and we observed that these IPC exosomes rescued the I/R injury in both normal and post-infarcted failing hearts. These data are consistent with a very recent in vitro study showing that the exosomes from non-diabetic plasma but not from diabetic plasma in humans protected rat cardiomyocytes from I/R injury.32 Exosomes possess a native structure and biocompatibility, and are less toxic and less immunogenic. These advantages make them ideal candidates for the development of cardioprotective interventions.33 Further, as a cell-free therapeutic approach, exosomes are gaining more and more interest in clinics as delivery vehicles that transfer drugs and bioactive molecules for treatment of cardiovascular diseases.13 Therefore, IPC exosomes from normal donors could be a promising therapeutic strategy for clinical patients with comorbidities, particularly heart failure.

Pro-survival kinases, including PI3K/Akt and ERK1/2, play an important role in regulating cardiomyocyte apoptosis.24 There is increasing evidence that exosomal microRNAs and proteins contribute to IPC-mediated cardioprotection by activating the Akt and ERK1/2 signals.15,34,35 In addition to serving as an exosome marker, the HSP70 protein of exosomes has been shown to interact with recipient cells to promote survival signals.35,36 Our results showed that exosomal HSP70 protein was upregulated by IPC, which may result in the activation of ERK signalling in the recipient cardiomyocytes.35 We also observed that IPC exosomes from normal rats increased the phosphorylation levels of ERK in both normal and failing recipient hearts after ex vivo I/R injury.

Previous studies have revealed the impairment of Akt signalling in post-infarcted, failing, ageing, and diabetic hearts.9,12,37 In contrast, we found that IPC exosomes effectively activated Akt in both normal hearts and post-infarcted failing hearts. These observations are consistent with several previous studies that endothelial and mesenchymal stem cell-derived exosomes enhanced cardiac function and inhibited cardiomyocyte apoptosis through activation of Akt signalling in post-infarcted hearts.38,39 Overall, the data from our and others suggest that the activation of Akt and ERKs by IPC exosomes may be involved in the cardioprotective effects in both normal and post-infarcted failing rat hearts.

There are several limitations in our present study. Firstly, we cannot completely rule out the interference of microvesicles (>200 nm) on the results. Such large microvesicles may have detrimental effects that are pro-thrombotic and pro-inflammatory.14 In this regard, it is not totally unexpected that one earlier study reported that remote IPC-derived microparticles failed to decrease infarct size.40 The size of the exosomes tested in the present study was found to be within a range of 10–100 nm. Secondly, we only tested single dose of GW4869 at 2 mg kg−1 following the experimental design of several previous studies, and we verified the inhibitory effects of GW4869 by detecting exosome content and exosome marker expression.18, 19, 20 Thirdly, IPC may promote the secretion of exosomes from different cells, including cardiomyocytes, endothelial cells, and cardiac fibroblasts, to the heart, and these exosomes derived from different cells may carry various cargos.41 Screening and identification of critical components in exosomes that contribute to cardioprotection would provide mechanistic insights into the cardioprotective effects of IPC exosomes, which should be carried out in future investigations. Finally, we observed similar morphology and size distribution of plasma exosomes from rats with heart failure relative to normal rats (Supplementary Fig. S3). However, we did not examine the effects of IPC exosomes from heart failure rats on I/R injury, as it was difficult to perform IPC stimulus on the post-infarcted hearts with massive scar formation. Future studies using remote IPC operation and different heart failure models are needed to explore the therapeutic value of IPC exosomes from animals and humans with heart failure.

In summary, our results suggest that ischaemic preconditioning-induced cardioprotective effect is, at least in part, dependent on the release of exosomes. Ischaemic preconditioning exosomes from normal rats retained the ability to protect post-infarcted failing hearts against I/R injury, and the mechanism is associated with the activation of the pro-survival kinases ERK1/2 and Akt. These findings provide a promising cardioprotective strategy for preventing ischaemic injury in patients with chronic heart failure.

Authors' contributions

Study conception: SH, SJ

Study design: SH, SJ

Performance of experiments: ZL, CW, XH, JC, ZL, CG, RZ, SJ

Data collection: ZL, XH, CW, SJ

Initial data analysis: ZL, XH, CW, SJ

Final data analysis: ZL, XH, SJ, SH, LZ

Writing of article: ZL, XH, SJ, SH, LZ

Critical revision of article: YZ, SH, LZ

Acknowledgements

The authors thank the Research Center of the Second Affiliated Hospital of Anhui Medical University for providing the instruments.

Handling editor: Gareth Ackland

Footnotes

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.bja.2022.08.040.

Contributor Information

Shiyun Jin, Email: xingzheruyun@126.com.

Shufang He, Email: sfhe@ahmu.edu.cn.

Declaration of interest

The authors declare that they have no conflicts of interest.

Funding

National Natural Science Foundation of China, China (81801938) to SJ; Key Program of Natural Science Foundation of Higher Education Institutions of Anhui Province, China (KJ2020A0212) to SH; Second Hospital of Anhui Medical University Seed Grant, China (2019GMFY01) to SH; Research Fund of Anhui Institute of Translational Medicine, China (2021zhyx-C42) to SH; Clinical Research Cultivation Program of the Second Hospital of Anhui Medical University, China (2021LCYB01) to SJ.

Appendix A. Supplementary data

The following is the Supplementary data to this article:

Multimedia component 1
mmc1.docx (2MB, docx)

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