Published online May 26, 2026. doi: 10.4252/wjsc.v18.i5.116611
Revised: January 12, 2026
Accepted: February 24, 2026
Published online: May 26, 2026
Processing time: 190 Days and 5.3 Hours
Accumulating studies suggest that mesenchymal stem cell (MSC)-derived extracellular vesicles mitigate myocardial injury by modulating intercellular communication pathways. Notably, exosomes from hypoxia-preconditioned MSCs (HPC-Exo) demonstrate superior therapeutic efficacy in ischemic heart disease compared with those from normoxic MSCs although the underlying molecular mechanisms remain largely unclear.
To investigate the cardioprotective effects of HPC-Exo on myocardial ische
Exosomes from MSCs cultured under normoxic or hypoxic conditions were isolated and characterized by electron microscopy and surface marker analysis. Cardioprotective effects were evaluated in hypoxia/reperfusion-treated cardiomyocytes and a murine I/R model with cardiac function assessed by echocardiography. MicroRNA se
HPC-Exo significantly attenuated myocardial I/R injury and improved cardiac function. Next-generation sequencing identified miR-29b-3p as highly enriched in HPC-Exo. Overexpression of miR-29b-3p alleviated hypoxia/reperfusion-induced cellular injury, reduced mitochondrial damage, and promoted mitophagy. Mechanistically, the PINK1/Parkin pathway mediated these protective effects. Knockdown of PINK1 suppressed Parkin expression, impaired mitophagy, and exacerbated reperfusion injury, ultimately diminishing the protective effects of miR-29b-3p.
Our findings demonstrated that HPC-Exo protect against myocardial I/R injury primarily through miR-29b-3p-mediated activation of PINK1/Parkin-dependent mitophagy.
Core Tip: This study identified hypoxia-preconditioned mesenchymal stem cell-derived exosomes as a potent therapeutic strategy for myocardial ischemia/reperfusion injury. High-throughput sequencing revealed miR-29b-3p as a key protective cargo that restores mitochondrial homeostasis by activating PINK1/Parkin-dependent mitophagy. miR-29b-3p significantly reduced oxidative stress, preserved mitochondrial integrity, and improve cardiac function in vivo, highlighting a promising exosome-based and mitochondria-targeted approach for future cardioprotection.
- Citation: Wen W, Liu CX, Wang Y, Lu XJ, Yang C, Chen SJ, Jin ZT, Qu MY, Deng JY, Zhang Z. Hypoxia-preconditioned mesenchymal stem cell-derived exosomes attenuate myocardial ischemia/reperfusion injury by miR-29b-3p via PINK1/Parkin-mediated mitophagy. World J Stem Cells 2026; 18(5): 116611
- URL: https://www.wjgnet.com/1948-0210/full/v18/i5/116611.htm
- DOI: https://dx.doi.org/10.4252/wjsc.v18.i5.116611
Myocardial ischemia remains a major cause of morbidity and mortality worldwide, posing a substantial threat to public health[1]. Currently, thrombolytic therapy and percutaneous coronary intervention are widely used to restore coronary perfusion and salvage ischemic myocardium[2]. However, abrupt reperfusion following prolonged ischemia can paradoxically aggravate myocardial injury, known as ischemia/reperfusion (I/R) injury[3]. This process involves excessive oxidative stress, inflammation, and cardiomyocyte apoptosis, ultimately leading to adverse cardiac remodeling and heart failure[3]. Preclinical and emerging clinical investigations suggest that mesenchymal stromal cells isolated from bone marrow exert beneficial effects on myocardial regeneration and functional recovery[4,5]. Nevertheless, accumulating evidence suggests that their benefits primarily arise from paracrine effects rather than direct differentiation into cardiomyocytes[6,7].
Among the key paracrine mediators released by mesenchymal stem cells (MSCs), exosomes (Exos) are nanoscale extracellular vesicles (30-150 nm) that facilitate intercellular communication[8]. MSC-derived Exos (MSC-Exo) carry bioactive molecules, including proteins, lipids, and microRNAs (miRNAs), which regulate diverse pathological processes[9]. They exert cardioprotective effects such as anti-apoptotic, anti-inflammatory, and pro-angiogenic activities, thereby avoiding the risks associated with direct cell transplantation[9]. Bone marrow-derived MSC-Exos have demonstrated therapeutic efficacy in myocardial ischemia models by modulating multiple signaling pathways[10]. Specific miRNAs, including miR-22, miR-24, miR-185, and miR-21-5p, reduce infarct size, inhibit apoptosis, promote angiogenesis, and preserve cardiac function[11,12]. However, unmodified MSC-Exos display limited reparative capacity[13] that can be enhanced by hypoxic preconditioning (HPC). HPC induces MSCs to release Exos enriched with pro-angiogenic and cytoprotective factors, yielding hypoxia-preconditioned MSC-derived Exos (HPC-Exo) with superior regenerative potential[14]. Nevertheless, the miRNA profiles of HPC-Exo and their mechanisms in myocardial repair remain incompletely understood.
In this study, we evaluated the cardioprotective effects of HPC-Exo against I/R injury. High-throughput sequencing revealed miR-29b-3p as a key enriched miRNA. Given the established protective roles of the miR-29b family in the heart, such as ameliorating injury, fibrosis, and apoptosis via the miR-29b-3p/HMCN1 axis (Han et al[15]) and mitigating I/R injury by targeting phosphatase and tensin homolog (Li et al[16]), we focused on elucidating the specific mechanism of miR-29b-3p in our model. In vivo, local delivery of miR-29b-3p markedly improved cardiac function, reduced myocardial fibrosis, and promoted tissue regeneration in I/R-injured mice. These results revealed a pivotal role for miR-29b-3p in myocardial protection and supported HPC-Exo as a promising therapeutic approach for myocardial I/R injury.
Four-week-old male C57BL/6J mice were used for all experiments. All animal tests were performed in compliance with the ethical norms and protocols sanctioned by the Ethics Committee of the PLA Rocket Force Characteristic Medical Center (Approval No. KY202527).
Mice were anesthetized and subjected to left anterior descending coronary artery ligation for 45 min followed by reperfusion. Sham-operated mice underwent thoracotomy only. At the onset of reperfusion, normoxic Exo or HPC-Exo (10 μL, 2 μg/μL; total 20 μg) was administered via intramyocardial multi-site injection with the dose determined based on preliminary experiments and previous reports. Mice were maintained at 37 °C and monitored for 24 h after surgery[17,18].
After I/R, 1% Evans blue was injected for 5 min. Hearts were excised, sliced, and stained with 2% triphenyltetrazolium chloride (TTC); viable myocardium appeared red, infarcted white, and non-ischemic blue. Evans blue/TTC staining was performed to visualize the area at risk and infarcted myocardium. The staining results were used for qualitative evaluation with representative images presented. No quantitative analysis of infarct size was conducted.
Echocardiography was performed under anesthesia using a high-resolution system. Mice were positioned on a warming platform, and their chest hair was removed to obtain parasternal views for assessments of cardiac structure and function.
Bone marrow from 4-6-week-old C57BL/6J mice was flushed and cultured at 37 °C/5% CO2. Adherent cells were passaged at 70%-80% confluence using 0.25% trypsin-EDTA.
Passage 3 bone marrow-derived MSCs were grown to 70%-80% confluence, then cultured in Exo-depleted medium under 1% O2, 5% CO2, and 94% N2 for 24 h for HPC.
Frozen H9c2 cells were thawed, centrifuged, resuspended in culture medium, seeded into culture dishes, and incubated at 37 °C with 5% CO2. Upon reaching 70%-80% confluence, the cells were trypsinized and subcultured at a 1:2 to 1:3 ratio.
Supernatant was filtered (0.22 μm) and ultracentrifuged (100000 × g at 4 °C) for 2 h. The pellet was resuspended in PBS and analyzed by transmission electron microscopy (TEM; 50-150 nm, cup-shaped), western blot (CD9, Alix, TSG101), and nanoparticle tracking analysis for size and concentration using fluorescent beads (68-155 nm).
Exosomal RNA was extracted, converted to cDNA, amplified by PCR, checked for quality, and sequenced on Illumina NovaSeq. Reads were aligned to miRBase for target prediction, functional annotation, and differential expression analysis.
H9c2 cells were washed with PBS, incubated in glucose-free Dulbecco’s Modified Eagle Medium under hypoxic conditions (1% O2, 5% CO2, 94% N2) for 12 h, then returned to complete Dulbecco’s Modified Eagle Medium and normoxic conditions (37 °C, 5% CO2, 21% O2).
Cells were treated in 96-well plates and incubated in Cell Counting Kit-8 solution for 2 h. Absorbance was measured at 450 nm to assess viability.
Cells at 70%-80% confluence were incubated with the corresponding staining working solutions [dihydroethidium (DHE), MitoSOX™, or (5,5’,6,6’-tetrachloro-1,1’,3,3’-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) dye] at 37 °C for 15-30 min in the dark, rinsed with PBS, counterstained with 4’,6-diamidino-2-phenylindole (DAPI) when required, and imaged under a fluorescence microscope (DHE: 535/610 nm; DAPI: 350/460 nm). For terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, mouse hearts were perfused with PBS, sectioned, fixed in 4% paraformaldehyde for 40 min, permeabilized with 0.5% Triton X-100, incubated with TUNEL reaction solution at 37 °C for 1 h, and visualized under green fluorescence.
Cells were stained with Mito-Tracker Green, fixed, permeabilized, blocked, incubated with LC3B antibody and secondary antibody, counterstained with DAPI, and imaged by confocal microscopy.
Flow cytometric analyses were employed to quantify intracellular redox status, programmed cell death, mitochondrial reactive oxygen species (ROS) generation, and alterations in mitochondrial electrochemical gradients. Cells were incubated with 5 μM DHE or 5 μM MitoSOX Red for 20 min at 37 °C to measure ROS. Apoptosis was evaluated by staining (1.0 × 106 to 1.5 × 106 cells with Annexin V-FITC and propidium iodide for 20 min at room temperature. Mi
Cells were fixed, embedded in 1% agarose, post-fixed with 1% osmium tetroxide, dehydrated, resin-embedded, sectioned at 60-80 nm, stained with uranyl acetate and lead citrate, and examined by TEM.
Exosomal RNA was extracted, dissolved in diethylpyrocarbonate water, and reverse-transcribed into cDNA. Reverse transcription quantitative PCR was performed using TAKARA RR820A, and relative miRNA expression was quantified using melting and amplification curves.
Cells were transfected with 20 μM PINK1 siRNA using a transfection reagent for 8 h, followed by medium replacement and 24-h culture. Knockdown efficiency was evaluated by western blot.
The PINK1 knockdown model was generated via tail vein injection of AAV9-cTNT-SaCas9-sgPINK1-EGFP (AAV9-sh-PINK1), and control mice received AAV9-cTNT-EGFP (AAV9-sh-NC). Knockdown efficiency was confirmed by western blot at 4 weeks post-injection.
Cells were lysed in radioimmunoprecipitation assay buffer with protease inhibitors, and the protein concentration was determined by bicinchoninic acid assay. Samples were separated on 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis, transferred to polyvinylidene fluoride membranes, blocked with 5% milk, and incubated overnight at 4 °C with primary antibodies: PINK1 (1:1000); Parkin (1:1000); Drp1 (1:1000); β-actin (1:5000); LC3B (1:1000); Tim23 (1:1000); and Tom20 (1:1000). After secondary antibody incubation, bands were developed with electrochemiluminescence and quantified using ImageJ.
GraphPad Prism 9 was used to perform statistical analyses (GraphPad Software, La Jolla, CA, United States). Data are expressed as the mean ± SD. One-way analysis of variance was used to evaluate differences across groups. Tukey’s post hoc test was utilized for analysis of pairwise comparisons. Statistical significance was defined as a P value less than 0.05.
Mouse bone marrow-derived MSCs were isolated and cultured under two distinct conditions: Normoxia (21% O2, 10% fetal bovine serum) and HPC (1% O2, 10% fetal bovine serum) for 24 h. Exos were subsequently purified from conditioned media via differential ultracentrifugation (Figure 1A). Nanoparticle tracking analysis revealed diameters of Exo and HPC-Exo within the canonical exosomal range (50-150 nm) (Figure 1B). The distinctive cup-shaped morphology of MSC-derived Exos was validated by TEM, and laser scattering microscopy further validated their spherical nanostructure (Figure 1C). Western blot analysis showed strong expression of the exosomal markers CD9, Alix, and Tsg101 in both Exo and HPC-Exo preparations, whereas little to no expression was detected in the supernatants of culture media under normoxic or hypoxic conditions (Figure 1D).
To evaluate the therapeutic efficacy of Exos in cardiac I/R injury, we created a mouse model by performing a 45-min closure of the left anterior descending artery, followed by reperfusion. Animals were randomized into four groups: Sham surgery; I/R control; Exo-treated (10 μg); and HPC-Exo-treated (10 μg) (Figure 2A). Infarct size via Evans blue/TTC dual staining confirmed significant myocardial salvage in HPC-Exo-treated mice compared with both I/R controls and Exo-treated counterparts (Figure 2B). Echocardiographic evaluation at 28 days post-I/R demonstrated the enhanced therapeutic benefits of HPC-Exo, including improved left ventricular dimensions (left ventricular end-diastolic diameter, left ventricular end-systolic diameter) and systolic function parameters (ejection fraction, fractional shortening) vs other groups (Figure 2C and D). TUNEL staining revealed substantial cardiomyocyte apoptosis in I/R hearts that was markedly attenuated by Exo administration with HPC-Exo demonstrating superior anti-apoptotic efficacy compared with standard Exo (Figure 2E and F).
An in vitro hypoxia/reperfusion (H/R) model was established to mimic myocardial I/R injury (Figure 2G). Fluo
This study aimed to systematically characterize the mechanistic pathways through which HPC-derived Exos confer myocardial protection. The miRNA profiles of HPC-Exo and Exo were compared using high-throughput next-generation sequencing. Total RNA was extracted from both groups, and differential expression analysis was performed. Considering that Exos exert biological functions mainly through the transfer of cell-specific proteins, mRNAs, and miRNAs, attention was focused on miRNAs significantly upregulated in HPC-Exo (Figure 3A). Next-generation sequencing revealed 12 miRNAs with markedly elevated expression in HPC-Exo compared with Exo (Figure 3B and C). We validated the differential expression of these miRNAs by quantitative PCR, confirming significant upregulation of four miRNAs (P < 0.05) (Figure 3D). To assess their functional relevance, each miRNA was overexpressed in cardiomyocytes and apoptosis was evaluated after H/R injury. Among them, miR-29b-3p exerted the strongest anti-apoptotic effect, markedly reducing H/R-induced apoptosis (Figure 3E and F). We subsequently evaluated oxidative stress levels, and similar to its anti-apoptotic effects, miR-29b-3p markedly attenuated H/R-induced oxidative stress in cardiomyocytes (Figure 3G-I). These findings highlighted miR-29b-3p as a key mediator of the cardioprotective effects of HPC-Exo, suggesting its potential as a therapeutic target for cardiac ischemia/reperfusion damage.
To explore the mechanisms of miR-29b-3p mediated cardioprotection during ischemia/reperfusion, a treatment group was established by overexpressing miR-29b-3p in cardiomyocytes (Figure 4A), followed by transcriptomic sequencing. miR-29b-3p was significantly enriched in functions related to response to oxygen-containing compounds, protein deubiquitination in ubiquitin-dependent catabolic processes, and mitochondrion-targeting sequence binding (Figure 4B). The PINK1/Parkin pathway is a central mechanism regulating mitophagy. Upon mitochondrial damage PINK1 stabilizes on the outer membrane and activates Parkin, which mediates ubiquitin chain tagging of the impaired mitochondria. These ubiquitin signals are recognized by autophagy receptors, ultimately directing autophagosomes to engulf and degrade the targeted mitochondria, thereby maintaining cellular homeostasis. These findings suggest that miR-29b-3p may protect cardiomyocytes primarily by restoring mitochondrial function.
To evaluate the effect of miR-29b-3p on mitochondrial integrity under H/R conditions, we first examined mito
ΔΨm, an indicator of mitochondrial function, was evaluated using JC-1 staining. ΔΨm was assessed using JC-1 staining. H/R and miR-NC groups showed decreased ΔΨm with reduced JC-1 aggregates (red) and increased monomers (green), whereas miR-29b-3p treatment restored ΔΨm, indicating partial recovery of mitochondrial function (Figure 4H). Flow cytometry confirmed higher ΔΨm in miR-29b-3p treated cells (Figure 4I and J). Western blot analysis further confirmed these findings. miR-29b-3p treatment significantly increased the expression of Parkin, PINK1, and Tim23, key regulators of mitophagy and mitochondrial quality control. The upregulation of PINK1/Parkin indicates enhanced mitophagy, and increased Tim23 suggests improved mitochondrial membrane stability and turnover (Figure 4K and L).
To investigate whether the cardioprotective effect of miR-29b-3p depends on PINK1/Parkin pathway-mediated mitophagy, we further examined the involvement of this signaling cascade by modulating key components of the pathway during myocardial I/R injury. We used Mdivi-1, a selective inhibitor of Drp1-mediated mitochondrial fission and mitophagy. Mdivi-1 treatment effectively suppressed mitochondrial fission and autophagy (Figure 5A). We then evaluated mitochondrial oxidative stress and apoptosis under these conditions. Mdivi-1 administration significantly increased mitochondrial ROS levels and apoptosis in all groups, particularly in the H/R and H/R + miR-29b-3p groups, thereby weakening the protective effects of miR-29b-3p. These results suggest that the cardioprotective action of miR-29b-3p against H/R-induced injury is at least partially mediated through mitophagy induction to remove damaged mitochondria (Figure 5B-D).
To further elucidate the role of PINK1 in mediating the protective effects of miR-29b-3p on H9c2 cells under H/R conditions, PINK1 expression was specifically silenced using siRNA (Figure 5E). Western blot analysis confirmed efficient PINK1 knockdown, accompanied by a concomitant decrease in Parkin expression in cells transfected with PINK1 siRNA. In contrast, miR-29b-3p treatment markedly upregulated both PINK1 and Parkin protein levels compared with the H/R group. Moreover, miR-29b-3p restored the H/R-induced alterations in autophagy-related and mitochondria-related proteins as demonstrated by an increased LC3-II/I ratio and reduced expression of Tim23 and Tom20. Importantly, these beneficial effects were partially reversed by PINK1 silencing, suggesting that PINK1 plays a critical role in miR-29b-3p mediated regulation of mitochondrial dynamics and autophagic activity (Figure 5E and F).
Furthermore, flow cytometry was performed to assess apoptosis (Figure 5G and H) and mitochondrial oxidative stress (Figure 5I and J) among the indicated groups, including Control, Control + PINK1 siRNA, H/R, H/R + PINK1 siRNA, H/R + miR-29b-3p, and H/R + miR-29b-3p + PINK1 siRNA. The results revealed that PINK1 silencing markedly increased both mitochondrial oxidative stress and apoptotic cell death across all experimental groups with the most pronounced effects observed in the H/R and H/R + miR-29b-3p groups. Notably, the knockdown of PINK1 almost completely abolished the cytoprotective effects of miR-29b-3p, highlighting the pivotal role of the PINK1/Parkin pathway in mediating miR-29b-3p induced cardioprotection.
To further validate the therapeutic effects of miR-29b-3p in vivo, we constructed a PINK1 knockdown mouse model by tail vein injection of AAV9-sh-PINK1 (Figure 5K). Myocardial infarction and ischemic areas were evaluated using Evans blue/TTC double staining (Figure 5L). The results showed that miR-29b-3p markedly reduced the myocardial ischemic area induced by I/R injury, whereas PINK1 knockdown diminished this therapeutic benefit. Moreover, echocardiographic assessment at 28 days post-I/R revealed that miR-29b-3p significantly improved cardiac function compared with other injury groups, and PINK1 knockdown partially suppressed this improvement (Figure 5M). Collectively, these findings indicated that miR-29b-3p exerts its cardioprotective effects under H/R stress by preserving mitochondrial quality control and functional integrity at least in part through activation of the PINK1/Parkin pathway.
This study provided compelling evidence that HPC-Exo enhances cardioprotective effects against myocardial I/R injury compared with Exo. Our major findings were as follows. First, intramyocardial injection of HPC-Exo significantly reduced myocardial infarct size and ischemic area while improving left ventricular ejection fraction as evidenced by Evans blue/TTC staining and echocardiography. Second, in vitro HPC-Exo treatment markedly decreased apoptosis and oxidative stress in H/R-treated cardiomyocytes, confirming their robust cytoprotective capacity. Third, miRNA sequencing revealed that miR-29b-3p was markedly enriched in HPC-Exo and acted as the key effector molecule mediating these effects via activation of PINK1/Parkin-dependent mitophagy.
Myocardial I/R injury remains one of the major clinical challenges in cardiovascular medicine. While early reperfusion therapy is indispensable for restoring blood flow to the ischemic myocardium, it paradoxically triggers a cascade of deleterious processes, including oxidative stress, calcium overload, mitochondrial dysfunction, and inflammatory injury, ultimately resulting in cardiomyocyte death and heart failure[19]. Despite the use of pharmacological agents and percutaneous coronary intervention, current treatments primarily address macroscopic reperfusion but fail to prevent the downstream molecular events leading to irreversible damage. In recent years stem cell-derived Exos have emerged as an attractive alternative to stem cell transplantation, offering similar paracrine benefits while avoiding the limitations of immune rejection, arrhythmogenic risk, and poor engraftment[20]. Exos carry a complex cargo of bioactive molecules, including proteins, lipids, and RNAs, that can modulate recipient cell behavior and promote cardiac repair[21].
In the present study, HPC substantially altered the molecular composition of bone marrow-derived MSC-derived Exos, enhancing their reparative efficacy. Among 12 significantly upregulated miRNAs in HPC-Exo, miR-29b-3p was identified as the principal effector. Functional validation confirmed that direct transfection of miR-29b-3p mimics reproduced the cytoprotective effects of HPC-Exo, whereas its inhibition abolished these effects. These findings are consistent with the results of Hou et al[22], who demonstrated that miR-29b-3p alleviated ischemic brain injury by reducing neuronal apoptosis and enhancing angiogenesis. Thus, our results revealed that HPC enriches exosomal miR-29b-3p, which may serve as a potent regulator of cardiomyocyte survival and mitochondrial integrity under ischemic stress.
Mitochondrial quality control is essential for maintaining cardiac energy homeostasis, with mitophagy, a selective form of autophagy, playing a pivotal role in removing dysfunctional mitochondria under stress conditions such as ischemia and oxidative injury[23,24]. Functional enrichment analysis revealed that cells treated with miR-29b-3p were significantly enriched in protein deubiquitination within ubiquitin-dependent catabolic processes and mitochondrion-targeting sequence binding. These enriched pathways suggest miR-29b-3p may regulate mitochondrial quality control via ubi
To further clarify the mechanistic basis of miR-29b-3p mediated cardioprotection, we employed Mdivi-1, a selective inhibitor of Drp1-dependent mitochondrial fission, to indirectly disrupt mitophagy[25]. The results indicated that Mdivi-1 treatment significantly attenuated the protective effects of miR-29b-3p as evidenced by increased mitochondrial oxidative stress and apoptosis. Given that the impairment of fission (by Mdivi-1) negated the benefit of miR-29b-3p and considering the central role of the PINK1/Parkin axis in mitophagy, our finding suggested that miR-29b-3p exerts protection at least in part by activating this specific pathway to clear damaged mitochondria.
During mitochondrial depolarization PINK1 stabilizes on the outer mitochondrial membrane and facilitates the recruitment of Parkin, which ubiquitinates key mitochondrial surface proteins, thereby targeting dysfunctional mitochondria for autophagy-mediated clearance[26,27]. Appropriate activation of mitophagy prevents excessive ROS accumulation and preserves mitochondrial function, thereby limiting cell death[28,29]. However, excessive or insufficient mitophagy can contribute to pathological remodeling in cardiac disease[30]. In this study miR-29b-3p treatment enhanced the colocalization of LC3 and Mito-Tracker, indicating increased mitophagosome formation. Western blot analysis confirmed upregulation of PINK1, Parkin, and Tim23, and Drp1 inhibition or PINK1 knockdown abolished these effects, demonstrating that miR-29b-3p regulates mitophagy primarily through the PINK1/Parkin pathway.
These findings are consistent with those of Sarkar et al[31], who reported that dysregulation of miR-29b-3p caused mitochondrial fragmentation and oxidative stress in dopaminergic neurons. Similarly, suppression of SLC39A7 or FOXO3 has been shown to inhibit mitophagy and aggravate I/R injury[32,33], whereas activation of PINK1/Parkin-dependent mitophagy ameliorates cardiac dysfunction by promoting mitochondrial clearance and reducing apoptosis[34]. Collec
Although functional evidence links miR-29b-3p to PINK1/Parkin-dependent mitophagy, the precise molecular mechanism by which miR-29b-3p regulates this signaling axis requires further clarification. In the present study we established a functional and pathway-level association between miR-29b-3p and PINK1/Parkin-mediated mitophagy rather than a direct miRNA-mRNA interaction. Specifically, miR-29b-3p overexpression markedly increased PINK1 and Parkin expression, promoted mitophagic activity, and attenuated mitochondrial oxidative stress and cardiomyocyte apoptosis, whereas genetic silencing of PINK1 or pharmacological inhibition of mitophagy largely abolished these protective effects in vitro and in vivo. These findings indicate that PINK1/Parkin-dependent mitophagy represents a critical downstream effector of miR-29b-3p mediated cardioprotection.
Importantly, our study does not establish a direct molecular interaction between miR-29b-3p and core components of the PINK1/Parkin pathway. Therefore, it is more likely that miR-29b-3p regulates this pathway through indirect mechanisms. miRNAs exert pleiotropic regulatory effects by targeting upstream modulators, signaling intermediates, or negative regulators rather than core pathway proteins[37,38]. In this context, miR-29b-3p may influence mitochondrial quality control by modulating proteins involved in mitochondrial dynamics, ubiquitin-dependent protein turnover, or cellular stress responses, thereby creating a permissive intracellular environment that favors PINK1 stabilization and Parkin recruitment during ischemia/reperfusion injury[26,32,39].
Additionally, miR-29b-3p may contribute to mitochondrial homeostasis by attenuating oxidative stress-responsive signaling networks[21,22]. The reduced mitochondrial ROS and preserved ΔΨm observed in miR-29b-3p-treated cardiomyocytes may facilitate controlled activation of mitophagy, preventing excessive mitochondrial damage while avoiding indiscriminate mitochondrial degradation[24,39]. Such balanced regulation of mitochondrial turnover is particularly critical during the reperfusion phase when abrupt oxidative stress poses a major threat to cardiomyocyte survival[40].
Although miR-29b-3p serves as the principal effector in HPC-Exo-mediated cardioprotection, the synergistic actions of other exosomal components may further contribute to the observed effects[41]. For instance, miR-210-3p has been reported to promote angiogenesis[42], long noncoding RNA MALAT1 to suppress inflammation through nuclear factor kappa B modulation[43] and circHIPK3 to preserve cardiac function by stabilizing HuR and reducing p21 activity[44]. The combinatorial interplay of these molecules likely amplifies the reparative efficacy of hypoxia-preconditioned Exos. Nonetheless, the clinical translation of Exo-based therapy faces several challenges, including large-scale production, purification standardization, targeted delivery, and long-term biosafety[45,46]. Furthermore, the possibility of immune activation or oncogenic transformation associated with repeated administration warrants careful evaluation. Future investigations employing single-cell RNA sequencing and spatial transcriptomics could elucidate the cell-type-specific effects of Exo treatment within the myocardial microenvironment. In addition, the engineering of biomimetic or synthetic nanocarriers may enhance delivery precision and stability, paving the way for the next generation of Exo-inspired the
Limitations of our study should be acknowledged. First, we did not track the specific uptake of HPC-Exo by cardio
Our findings demonstrated that HPC-Exo alleviated mitochondrial dysfunction and oxidative stress by activating the PINK1/Parkin pathway through miR-29b-3p–mediated regulation of mitophagy, thereby attenuating myocardial I/R injury. This mechanism highlights the therapeutic potential of miR-29b-3p in cardioprotection and provides a novel strategy for the treatment of cardiovascular diseases.
The authors express their sincere gratitude to all the staff who contributed to this project for their efforts.
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