Ischemic heart-derived small extracellular vesicles impair adipocyte function
Open accessAbstract
Background: Patients with acute myocardial infarction suffer systemic metabolic dysfunction via incompletely understood mechanisms. Adipocytes play critical role in metabolic homeostasis. The impact of acute myocardial infarction upon adipocyte function is unclear. Small extracellular vesicles (sEVs) critically contribute to organ-organ communication. Whether and how small extracellular vesicle mediate post-MI cardiomyocyte/adipocyte communication remain unknown. Methods: Plasma sEVs were isolated from sham control (Pla-sEV Sham ) or 3 hours after myocardial ischemia/reperfusion (Pla-sEV MI/R ) and incubated with adipocytes for 24 hours. Compared with Pla-sEV Sham , Pla-sEV MI/R significantly altered expression of genes known to be important in adipocyte function, including a well-known metabolic regulatory/cardioprotective adipokine, APN (adiponectin). Pla-sEV MI/R activated 2 (PERK-CHOP and ATF6 [transcription factor 6]-EDEM [ER degradation enhancing alpha-mannosidase like protein 1] pathways) of the 3 endoplasmic reticulum (ER) stress pathways in adipocytes. These pathological alterations were also observed in adipocytes treated with sEVs isolated from adult cardiomyocytes subjected to in vivo myocardial ischemia/reperfusion (MI/R) (Myo-sEV MI/R ). Bioinformatic/RT-qPCR analysis demonstrates that the members of miR-23-27-24 cluster are significantly increased in Pla-sEV MI/R , Myo-sEV MI/R , and adipose tissue of MI/R animals. Administration of cardiomyocyte-specific miR-23-27-24 sponges abolished adipocyte miR-23-27-24 elevation in MI/R animals, supporting the cardiomyocyte origin of adipocyte miR-23-27-24 cluster. In similar fashion to Myo-sEV MI/R , a miR-27a mimic activated PERK-CHOP and ATF6-EDEM-mediated ER stress. Conversely, a miR-27a inhibitor significantly attenuated Myo-sEV MI/R -induced ER stress and restored APN production. Results: An unbiased approach identified EDEM3 (ER degradation enhancing alpha-mannosidase like protein 3) as a novel downstream target of miR-27a. Adipocyte EDEM3 deficiency phenocopied multiple pathological alterations caused by Myo-sEV MI/R , whereas EDEM3 overexpression attenuated Myo-sEV MI/R -resulted ER stress. Finally, administration of GW4869 or cardiomyocyte-specific miR-23-27-24 cluster sponges attenuated adipocyte ER stress, improved adipocyte endocrine function, and restored plasma APN levels in MI/R animals. Conclusions: We demonstrate for the first time that MI/R causes significant adipocyte ER stress and endocrine dysfunction by releasing miR-23-27-24 cluster-enriched small extracellular vesicle. Targeting small extracellular vesicle–mediated cardiomyocyte-adipocyte pathological communication may be of therapeutic potential to prevent metabolic dysfunction after MI/R.
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The miR-23-27-24 cluster participates in endoplasmic reticulum stress within adipocytes and improves their endocrine function through targeting EDEM3.
“This cluster participate in endoplasmic reticulum stress within adipocytes and improve their endocrine function through protease targeting ER degradation enhancing alpha-mannosidase like protein 3 (EDEM3) [23].”
From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [23]
The Discussion says the miR-23-27-24 cluster causes adipocyte ER stress and endocrine dysfunction, not improved endocrine function. The EDEM3 section identifies EDEM3 as a miR-27 target and says its suppression is responsible for that dysfunction; inhibiting miR-27 instead restored endocrine function. (LLM, conf=0.93)
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Experimental — accuracy not yet measuredExpression levels of members of the miR-23-27-24 cluster are significantly increased in myocardial cells of patients with acute myocardial infarction.
“The expression levels of members within the miR-23-27-24 cluster are significantly increased in myocardial cells exhibiting this pathological manifestation.”
From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [23]
The miR-23-27-24 identification section and Figure 3 caption (page unavailable) report significant increases in the cluster in cardiomyocyte-derived vesicles and cardiac tissue after myocardial ischemia/reperfusion. Those results concern mice and an ischemia/reperfusion model; they do not establish the claimed increase in myocardial cells of patients with acute myocardial infarction. (LLM, conf=0.87)
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- Authors
- Gan, L., Liu, D., Xie, D., Bond Lau, W., Liu, J., Christopher, T. A., Lopez, B., Liu, L., Hu, H., Yao, P., He, Y., Gao, E., Koch, W. J., Zhao, J., Ma, X.-L., Cao, Y., & Wang, Y.
- Affiliations
- Thomas Jefferson University (US)
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (L.G., D.L., D.X., W.B.L., J.L., T.A.C., B.L., P.Y., J.Z., X.-L.M., Y.W.).
- Sichuan University (CN)
- Temple University (US)
- ORCID
- Venue
- Circulation Research
- Published
- 2022-01-07
- Volume
- 130
- Issue
- 1
- Pages
- 48-66
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W3211416842
- Cited by
- 80
- References
- 61
- Citations by year
- 2026: 13 · 2025: 19 · 2024: 24 · 2023: 13 · 2022: 11
- FWCI
- 3.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81772037, 82070421, 81801883, 82072135)
- Department of Science and Technology of Sichuan Province
- Sichuan University (ZYJC18019)
- West China Hospital, Sichuan University (1.3.5, ZYJC18019)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- acute myocardial infarction, small extracellular vesicles, adipocyte function, myocardial ischemia-reperfusion injury, adiponectin, endoplasmic reticulum stress, PERK/CHOP pathway, miR-27a, plasma vesicles
- MeSH terms
- Extracellular Vesicles, Animals, Cell Communication, Male, Membrane Proteins, Myocardial Infarction, Adipocytes, eIF-2 Kinase, Myocytes, Cardiac, MicroRNAs, Mice, Activating Transcription Factor 6, Transcription Factor CHOP, Adiponectin, Endoplasmic Reticulum Stress
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