Ischemic Heart-Derived Small Extracellular Vesicles Impair Adipocyte Function

Posted: 2021-11-12 20:00:00
Background: Acute myocardial infarction (AMI) patients suffer systemic metabolic dysfunction via incompletely understood mechanisms. Adipocytes play critical role in metabolic homeostasis. The impact of AMI upon adipocyte function is unclear. Small extracellular vesicles (sEV) critically contribute to organ-organ communication. Whether and how sEV mediate post-MI cardiomyocyte/adipocyte communication remain unknown.Methods Plasma sEV were isolated from sham control (Pla-sEVSham) or 3 hours after myocardial ischemia/reperfusion (Pla-sEVMI/R) and incubated with adipocytes for 24 hours. Compared to Pla-sEVSham, Pla-sEVMI/R significantly altered expression of genes known to be important in adipocyte function, including a well-known metabolic regulatory/cardioprotective adipokine, adiponectin (APN). Pla-sEVMI/R activated two (PERK-CHOP and ATF6-EDEM pathways) of the three 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 MI/R (Myo-sEVMI/R). Bioinformatic/RT-qPCR analysis demonstrates that the members of miR-23-27-24 cluster are significantly increased in Pla-sEVMI/R, Myo-sEVMI/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-sEVMI/R, a miR-27a mimic activated PERK-CHOP and ATF6-EDEM mediated ER stress. Conversely, a miR-27a inhibitor significantly attenuated Myo-sEVMI/R-induced ER stress and restored APN production. Results: An unbiased approach identified EDEM3 as a novel downstream target of miR-27a. Adipocyte EDEM3 deficiency phenocopied multiple pathological alterations caused by Myo-sEVMI/R, whereas EDEM3 overexpression attenuated Myo-sEVMI/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. Conclusion: 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 sEV. Targeting sEV-mediated cardiomyocyte-adipocyte pathologic communication may be of therapeutic potential to prevent metabolic dysfunction after MI/R.

参考サイト PubMed: exsome


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