Nicorandil-Pretreated Mesenchymal Stem Cell-Derived Exosomes Facilitate Cardiac Repair After Myocardial Infarction via Promoting Macrophage M2 Polarization by Targeting miR-125a-5p/TRAF6/IRF5 Signaling Pathway

Int J Nanomedicine. 2024 Feb 29:19:2005-2024. doi: 10.2147/IJN.S441307. eCollection 2024.

Abstract

Background: Exosomes derived from bone marrow mesenchymal stem cells (MSC-exo) have been considered as a promising cell-free therapeutic strategy for ischemic heart disease. Cardioprotective drug pretreatment could be an effective approach to improve the efficacy of MSC-exo. Nicorandil has long been used in clinical practice for cardioprotection. This study aimed to investigate whether the effects of exosomes derived from nicorandil pretreated MSC (MSCNIC-exo) could be enhanced in facilitating cardiac repair after acute myocardial infarction (AMI).

Methods: MSCNIC-exo and MSC-exo were collected and injected into the border zone of infarcted hearts 30 minutes after coronary ligation in rats. Macrophage polarization was detected 3 days post-infarction, cardiac function as well as histological pathology were measured on the 28th day after AMI. Macrophages were separated from the bone marrow of rats for in vitro model. Exosomal miRNA sequencing was conducted to identify differentially expressed miRNAs between MSCNIC-exo and MSC-exo. MiRNA mimics and inhibitors were transfected to MSCs or macrophages to explore the specific mechanism.

Results: Compared to MSC-exo, MSCNIC-exo showed superior therapeutic effects on cardiac functional and structural recovery after AMI and markedly elevated the ratio of CD68+ CD206+/ CD68+cells in infarcted hearts 3 days post-infarction. The notable ability of MSCNIC-exo to promote macrophage M2 polarization was also confirmed in vitro. Exosomal miRNA sequencing and both in vivo and in vitro experiments identified and verified that miR-125a-5p was an effector of the roles of MSCNIC-exo in vivo and in vitro. Furthermore, we found miR-125a-5p promoted macrophage M2 polarization by inhibiting TRAF6/IRF5 signaling pathway.

Conclusion: This study suggested that MSCNIC-exo could markedly facilitate cardiac repair post-infarction by promoting macrophage M2 polarization by upregulating miR-125a-5p targeting TRAF6/IRF5 signaling pathway, which has great potential for clinical translation.

Keywords: exosomes; macrophage polarization; mesenchymal stem cell; myocardial infarction; nicorandil.

MeSH terms

  • Animals
  • Exosomes* / metabolism
  • Interferon Regulatory Factors / metabolism
  • Macrophages / metabolism
  • Mesenchymal Stem Cells* / metabolism
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Myocardial Infarction* / pathology
  • Nicorandil / metabolism
  • Rats
  • Signal Transduction
  • TNF Receptor-Associated Factor 6 / metabolism

Substances

  • Nicorandil
  • TNF Receptor-Associated Factor 6
  • MicroRNAs
  • IRF5 protein, rat
  • Interferon Regulatory Factors

Grants and funding

This project was supported by the grants from the National Key Research and Development Program of China (No. 2017YFC1700503), CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-12M-1-009), the National Natural Science Foundation of China (Nos. 81573957, 81774292, 81874461, 82100313, 82300332 and 82070307), and NSFC Incubation Project of Guangdong Provincial People’s Hospital (KY0120220041).