Engineered Exosomes with Growth Differentiation Factor-15 Overexpression Enhance Cardiac Repair After Myocardial Injury

Int J Nanomedicine. 2024 Apr 6:19:3295-3314. doi: 10.2147/IJN.S454277. eCollection 2024.

Abstract

Background: Cardiac repair remains a thorny issue for survivors of acute myocardial infarction (AMI), due to the regenerative inertia of myocardial cells. Cell-free therapies, such as exosome transplantation, have become a potential strategy for myocardial injury. The aim of this study was to investigate the role of engineered exosomes in overexpressing Growth Differentiation Factor-15 (GDF-15) (GDF15-EVs) after myocardial injury, and their molecular mechanisms in cardiac repair.

Methods: H9C2 cells were transfected with GDF-15 lentivirus or negative control. The exosomes secreted from H9C2 cells were collected and identified. The cellular apoptosis and autophagy of H2O2-injured H9C2 cells were assessed by Western blotting, TUNEL assay, electron microscopy, CCK-8 and caspase 3/7 assay. A rat model of AMI was constructed by ligating the left anterior descending artery. The anti-apoptotic, pro-angiogenic effects of GDF15-EVs treatment, as well as ensuing functional and histological recovery were evaluated. Then, mRNA sequencing was performed to identify the differentially expressed mRNAs after GDF15-EVs treatment.

Results: GDF15-EVs inhibited apoptosis and promoted autophagy in H2O2 injured H9C2 cells. GDF15-EVs effectively decreased the infarct area and enhanced the cardiac function in rats with AMI. Moreover, GDF15-EVs hindered inflammatory cell infiltration, inhibited cell apoptosis, and promoted cardiac angiogenesis in rats with AMI. RNA sequence showed that telomerase reverse transcriptase (TERT) mRNA was upregulated in GDF15-EVs-treated H9C2 cells. AMPK signaling was activated after GDF15-EVs. Silencing TERT impaired the protective effects of GDF15-EVs on H2O2-injured H9C2 cells.

Conclusion: GDF15-EVs could fulfil their protective effects against myocardial injury by upregulating the expression of TERT and activating the AMPK signaling pathway. GDF15-EVs might be exploited to design new therapies for AMI.

Keywords: acute myocardial infarction; exosomes; growth differentiation factor-15; telomerase reverse transcriptase.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • AMP-Activated Protein Kinases / pharmacology
  • Animals
  • Apoptosis
  • Exosomes* / metabolism
  • Growth Differentiation Factor 15* / genetics
  • Growth Differentiation Factor 15* / metabolism
  • Growth Differentiation Factor 15* / pharmacology
  • Hydrogen Peroxide / metabolism
  • Hydrogen Peroxide / pharmacology
  • Myocardial Infarction* / genetics
  • Myocardial Infarction* / pathology
  • Myocardial Infarction* / therapy
  • Myocytes, Cardiac
  • RNA, Messenger / metabolism
  • Rats

Substances

  • AMP-Activated Protein Kinases
  • Growth Differentiation Factor 15
  • Hydrogen Peroxide
  • RNA, Messenger

Grants and funding

This study was supported by grants from the National Natural Science Foundation of China (Grant No.82270328), the Natural Science Foundation of Jiangsu Province (BK20221229), the Technology Development Fund of Nanjing Medical University (NMUB2020069), the Major Research plan of Changzhou Health Commission of Jiangsu Province of China (ZD202215), the Changzhou Sci & Tech Program (CE20225051), the China Postdoctoral Science Funding Program (2022M720544) and the Changzhou High-Level Medical Talents Training Project (2022CZBJ054).