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Extracellular vesicles carrying proinflammatory factors may spread atherosclerosis to remote locations

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Abstract

Most cells involved in atherosclerosis release extracellular vesicles (EVs), which can carry bioactive substances to downstream tissues via circulation. We hypothesized that EVs derived from atherosclerotic plaques could promote atherogenesis in remote locations, a mechanism that mimics the blood metastasis of cancer. Ldlr gene knockout (Ldlr KO) rats were fed on a high cholesterol diet and underwent partial carotid ligation to induce local atherosclerosis. EVs were separated from carotid artery tissues and downstream blood of carotid ligation by centrifugation. MiRNA sequencing and qPCR were then performed to detect miRNA differences in EVs from rats with and without induced carotid atherosclerosis. Biochemical analyses demonstrated that EVs derived from atherosclerosis could increase the expression of ICAM-1, VCAM-1, and E-selectin in endothelial cells in vitro. EVs derived from atherosclerosis contained a higher level of miR-23a-3p than those derived from controls. MiR-23a-3p could promote endothelial inflammation by targeting Dusp5 and maintaining ERK1/2 phosphorylation in vitro. Inhibiting EV release could attenuate atherogenesis and reduce macrophage infiltration in vivo. Intravenously administrating atherosclerotic plaque-derived EVs could induce intimal inflammation, arterial wall thickening and lumen narrowing in the carotids of Ldlr KO rats, while simultaneous injection of miR-23a-3p antagomir could reverse this reaction. The results suggested that EVs may transfer atherosclerosis to remote locations by carrying proinflammatory factors, particularly miR-23a-3p.

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Data availability

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Abbreviations

EVs:

Extracellular vesicles

EC:

Endothelial cell

miRNA:

MicroRNA

3′-UTR:

3′-Untranslated region

DUSP5:

Dual specificity phosphatase 5

MAPK:

Mitogen-activated protein kinase

Ldlr KO:

Ldlr Gene knockout

HFHC:

High fat high cholesterol

LCA:

Left carotid artery

TEM:

Transmission electron microscopy

ICAM-1:

Intercellular adhesion molecule-1

VCAM-1:

Vascular cell adhesion molecule-1

ERK:

Extracellular regulated kinase

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Acknowledgements

The authors thank Guangzhou Sagene Biotech Co., Ltd. for their technical assistance in making a pattern diagram.

Funding

This work was partly supported by the National Nature Science Foundation of China under Grant NSFC # 81870947 to GX and the National Nature Science Foundation of China under Grant NSFC # 81870946 to XL.

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Author notes

  1. Mengna Peng, Rui Sun, Ye Hong have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, China

    Mengna Peng, Jia Wang, Yi Xie, Xiaohao Zhang, Juanji Li, Yunzi Li, Xiaoke Wang, Ting Wan, Ying Zhao, Ruidong Ye, Qian Liu, Xinfeng Liu & Gelin Xu

  2. Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, 200433, China

    Rui Sun

  3. Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210002, Jiangsu, China

    Ye Hong

  4. Department of Neurology, Jinling Hospital, the First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, Jiangsu, China

    Hongquan Guo & Xinfeng Liu

  5. Division of Life Sciences and Medicine, Stroke Center & Department of Neurology, Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230036, Anhui, China

    Pengfei Xu & Xinfeng Liu

  6. Department of Neurology, Guilin People’s Hospital, Guilin, 541002, Guangxi, China

    Feihong Huang

  7. Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, 100191, China

    Yuhui Wang & George Liu

  8. Institute of Cardiovascular Sciences, School of Basic Medicine, Peking University Health Science Center, Beijing, 100191, China

    Yuhui Wang & George Liu

  9. Department of Neurology, Shenzhen Second People’s Hospital/First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, Guangdong, China

    Gelin Xu

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  1. Mengna Peng
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Correspondence to Xinfeng Liu or Gelin Xu.

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The study was approved by the Animal Subject Review Board of Jinling Hospital (2020JLHGKJDWLS-114) and was performed according to the Guide for National Institutes of Health for the Care and Use of Laboratory Animals.

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Peng, M., Sun, R., Hong, Y. et al. Extracellular vesicles carrying proinflammatory factors may spread atherosclerosis to remote locations. Cell. Mol. Life Sci. 79, 430 (2022). https://doi.org/10.1007/s00018-022-04464-2

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