DOI: 10.1161/circ.148.suppl_1.13754 ISSN: 0009-7322

Abstract 13754: Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles Alleviate Fibrosis by Reducing Energy Production of Cardiac Fibroblast via Glutamate Metabolism Regulation

yongjian chen, Jingyi Wang, Cheng Ni, Xin Yang Hu
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Background: Extracellular vesicles derived from bone marrow mesenchymal stem cells (MSC-EVs) have been validated for certain therapeutic effects on cardiac diseases, however, the underlying mechanism and precise bioactive components towards myocardial fibrosis remain unknown.

Aim: The current research endeavors to investigate the utilization of MSC-EVs in pressure overload induced fibrosis and unravel the mechanisms of MSC-EVs mediated fibrosis regulation.

Methods and Results: Compare to the control group, mice underwent intramyocardial injection of MSC-EVs showed remarkable improvement of cardiac function, as well as cardiac fibrosis post transverse aortic constriction (TAC) surgery. Seahorse XFe Extracellular Flux Analyzer unveiled decreased ATP production in fibroblasts after MSC-EVs administration in vitro . Targeted metabolomics and KEGG pathway analysis revealed glutamate metabolism as the predominantly metabolism process that regulated by MSC-EVs in cardiac fibroblasts. Meanwhile, cell metabolism assays indicated dysregulated α-ketoglutaric level in MSC-EVs treated fibroblasts, which directly lead to an activation of AMPK. Further screening identified glutamic pyruvate transaminase (GPT2) ,which catalyzes glutamic acid to α-ketoglutaric, to be pivotally suppressed by MSC-EVs treatment. Moreover, miR-30c-5p in MSC-EVs was uncovered to inhibit GPT2 expression. In the in vivo TAC model, MSC-EVs pretreated with the miR-30c-5p oligonucleotide did not recapitulated the same results as MSC-EVs do, while MSC-EVs with miR-30c-5p overexpression exerted better therapeutic effect than MSC-EVs alone.

Conclusions: MSC-EVs ameliorate cardiac fibrosis via reducing the synthesis of ATP from cardiac fibroblast, which in turn improve cardiac function in mice under pressure overload condition. This effect is mediated by miR-30c-5p in MSC-EVs through the inhibition of GPT2 expression and subsequent AMPK activation in cardiac fibroblasts.

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