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-sEV
Sham
) or 3 hours after myocardial ischemia/reperfusion (Pla-sEV
MI/R
) and incubated with adipocytes for 24 hours. Compared to 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, adiponectin (APN). Pla-sEV
MI/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-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 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.
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.
Venlafaxine, a novel third-generation antidepressant drug, has been described as a reference treatment for major depression, owing to its ability of inhibiting both noradrenalin and serotonin neuronal reuptake, and inhibiting dopamine reuptake slightly. However, its clinical application is hampered by a limited brain distribution. Glucosylation is an effective way to enhance the brain targeting ability of drugs, but the bidirectional transport of glucose transporter 1 (GLUT ) might decrease the concentrations of venlafaxine-glucose (V-G) in brain before the release of parent drug venlafaxine. To conquer this drawback of GLUT , "lock-in" thiamine disulfide system (TDS) was introduced to modify the V-G conjugate. Both conjugates could release venlafaxine when incubated with the various buffers, mice plasma, and brain homogenate. The evaluation in vivo demonstrated that venlafaxine-TDS-glucose (V-TDS-G) had an improved targeting ability and significantly increased the level of venlafaxine in brain compared to the naked venlafaxine and V-G. The relative uptake efficiency (RE) and concentration efficiency (CE) were enhanced to 5.69 and 5.70 times higher than that of naked venlafaxine, respectively. The results of this study suggest that the conjugate strategy based on the glucose-TDS (G-TDS) is available to enhance the delivery of central nervous system (CNS) drugs into brain.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.