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Differential Proteomic Profiles of Coronary Serum Exosomes in Acute Myocardial Infarction Patients with or Without Diabetes Mellitus: ANGPTL6 Accelerates Regeneration of Endothelial Cells Treated with Rapamycin via MAPK Pathways

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Abstract

Purpose

Delayed re-endothelialization after coronary drug-eluting stent implantation is associated with an increased incidence of late in-stent thrombosis. Serum exosomes exhibit controversial effects on promoting endothelialization. This study aimed to compare the angiogenic effects of serum exosomes derived from patients with acute myocardial infarction (AMI) and AMI plus diabetes mellitus (DM) and to explore the underlying mechanisms.

Methods

Serum exosomes derived from patients in the control (Con-Exos), AMI (AMI-Exos), and AMI plus DM (AMI+DM-Exos) groups were isolated and identified using standard assays. CCK-8, wound healing, and tube formation assays were performed to detect the angiogenic abilities of serum exosomes on rapamycin-conditioned human umbilical vein endothelial cells (HUVECs). Differential proteomic profiles between AMI-Exos and AMI+DM-Exos were analyzed by mass spectrometry. The effects and potential mechanisms of exosomal angiopoietin-like 6 (ANGPTL6) were investigated.

Results

Functional assays indicated that compared with Con-Exos, AMI-Exos enhanced, whereas AMI+DM-Exos inhibited the cell proliferation, migration, and tube formation of rapamycin-conditioned HUVECs. Subsequently, 28 differentially expressed proteins between AMI-Exos and AMI+DM-Exos were identified, which were correlated with material transportation, immunity, and inflammatory reaction. Moreover, ANGPTL6 was highly enriched in AMI-Exos. Overexpression and knockdown of ANGPTL6 enhanced and inhibited angiogenesis, respectively. Furthermore, the effect of ANGPTL6 on angiogenesis was mediated via the activation of ERK 1/2, JNK, and p38 pathways. The inhibition of ERK 1/2 signaling markedly attenuated the migration abilities of overexpressing ANGPTL6.

Conclusion

Diabetes impairs the regenerative capacities of serum exosomes. Exosomal ANGPTL6 contributes to endothelial repair and is a novel therapeutic target for enhanced stent endothelization.

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Data Availability

The data used to support the findings of this study are available from the corresponding authors upon request.

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Funding

This work was supported by the National Natural Science Foundation of China (Grant number 81970281), Academic Promotion Programme of Shandong First Medical University (Grant number 2019QL012), Natural Science Foundation of Shandong Province (Grant number ZR2021QH130), and Projects of Medical and Health Technology Development Program in Shandong province (Grant number 2017WS087).

Author information

Authors and Affiliations

  1. Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766 Jingshi Road, Jinan, 250014, China

    Weizong Wang, Yixin Zhao, Pengju Zhu, Xiaomeng Jia, Cong Wang, Qingbin Zhang, Hao Li, Jiangrong Wang & Yinglong Hou

Authors
  1. Weizong Wang
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  2. Yixin Zhao
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  3. Pengju Zhu
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  4. Xiaomeng Jia
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  5. Cong Wang
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  6. Qingbin Zhang
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  7. Hao Li
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  8. Jiangrong Wang
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  9. Yinglong Hou
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Contributions

Weizong Wang, Jiangrong Wang, and Yinglong Hou designed the study. Weizong Wang, Yixin Zhao, and Pengju Zhu performed the experiments, collected, and assembled data. Weizong Wang wrote the manuscript. Xiaomeng Jia analyzed and interpreted the data. Cong Wang prepared all the figures. Qingbin Zhang participated in editing the manuscript. Hao Li provided technical support. All authors reviewed and approved the final version of the manuscript.

Corresponding authors

Correspondence to Jiangrong Wang or Yinglong Hou.

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Ethics Approval

The study design was approved by The Ethics Committee of The First Affiliated Hospital of Shandong First Medical University. The procedures used in this study were in accordance with the tenets of the 1964 Helsinki Declaration.

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Written informed consent was acquired from all individual participants included in the study.

Competing Interests

The authors declare no competing interests.

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Supplementary information

Supplementary Fig. 1

Transfection efficiency of ANGPTL6 overexpression plasmid in HUVECs treated with rapamycin. **P < 0.001 (PNG 130 kb)

High resolution image (TIF 160 kb)

Supplementary Fig. 2

Comparison of different ANGPTL6 siRNAs for transfection efficiency in HUVECs treated with rapamycin. **P < 0.001. CON = scramble control (PNG 111 kb)

High resolution image (TIF 149 kb)

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Wang, W., Zhao, Y., Zhu, P. et al. Differential Proteomic Profiles of Coronary Serum Exosomes in Acute Myocardial Infarction Patients with or Without Diabetes Mellitus: ANGPTL6 Accelerates Regeneration of Endothelial Cells Treated with Rapamycin via MAPK Pathways. Cardiovasc Drugs Ther 38, 13–29 (2024). https://doi.org/10.1007/s10557-022-07365-5

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