Percutaneous Intracoronary Delivery of Plasma Extracellular Vesicles Protects the Myocardium against Ischemia-Reperfusion Injury in Canis

Hongyun Wang; Rusitanmujiang Maimaitiaili; Jianhua Yao; Yuling Xie; Sujing Qiang; Fan Hu; Xiang Li; Chao Shi; Peng Jia; Haotian Yang; Meng Wei; Juan Zhao; Zheng Zhou; Jinxin Xie; Jizong Jiang; Haidong Cai; Joost P.G. Sluijter; Yawei Xu; Yi Zhang; Junjie Xiao

doi:10.1161/HYPERTENSIONAHA.121.17574

Percutaneous Intracoronary Delivery of Plasma Extracellular Vesicles Protects the Myocardium against Ischemia-Reperfusion Injury in Canis

Hongyun Wang, Rusitanmujiang Maimaitiaili, Jianhua Yao, Yuling Xie, Sujing Qiang, Fan Hu, Xiang Li, Chao Shi, Peng Jia, Haotian Yang, Meng Wei, Juan Zhao, Zheng Zhou, Jinxin Xie, Jizong Jiang, Haidong Cai, Joost P.G. Sluijter, Yawei Xu, Yi Zhang, Junjie Xiao^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

1 Citation (Scopus)

Abstract

Plasma circulating extracellular vesicles (EVs) have been utilized as a potential therapeutic strategy to treat ischemic disease through intramyocardial injection (efficient but invasive) or tail vein injection (noninvasive but low cardiac retention). An effective and noninvasive delivery of EVs for future clinical use is necessary. The large animal (canine) model was complemented with a murine ischemia-reperfusion injury (IRI) model, as well as H9 human embryonic stem cell-induced cardiomyocytes or neonatal rat cardiomyocytes to investigate the effective delivery method and the role of plasma EVs in the IRI model. We further determine the crucial molecule within EVs that confers the cardioprotective role in vivo and in vitro and investigate the efficiency of CHP (cardiac homing peptide)-linked EVs in alleviating IRI. D-SPECT imaging showed that percutaneous intracoronary delivery of EVs reduced infarct extent in dogs. CHP-EVs further reduced IRI-induced cardiomyocyte apoptosis in mice and neonatal rat cardiomyocytes. Mechanistically, administration of EVs by percutaneous intracoronary delivery (in dog) and myocardial injection (in mice) just before reperfusion reduced infarct size of IRI by increasing miR-486 levels. miR-486-deleted EVs exacerbated oxygen-glucose deprivation/reoxygenation-induced human embryonic stem cell-induced cardiomyocytes and neonatal rat cardiomyocyte apoptosis. EV-miR-486 inhibited the PTEN (phosphatase and tensin homolog deleted on chromosome ten) expression and then promoted AKT (protein kinase B) activation in human embryonic stem cell-induced cardiomyocytes and neonatal rat cardiomyocytes. In conclusion, plasma-derived EVs convey miR-486 to the myocardium and attenuated IRI-induced infarction and cardiomyocyte apoptosis. CHP strategy was effective to improve cardiac retention of EVs in mice (in vivo) and dogs (ex vivo).

Original language	English
Pages (from-to)	1541-1554
Number of pages	14
Journal	Hypertension
Volume	78
Issue number	5
DOIs	https://doi.org/10.1161/HYPERTENSIONAHA.121.17574
Publication status	Published - Nov 2021

Keywords

extracellular vesicles
infarction
microRNA
plasma
reperfusion injury

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10.1161/HYPERTENSIONAHA.121.17574

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Wang, H., Maimaitiaili, R., Yao, J., Xie, Y., Qiang, S., Hu, F., Li, X., Shi, C., Jia, P., Yang, H., Wei, M., Zhao, J., Zhou, Z., Xie, J., Jiang, J., Cai, H., Sluijter, J. P. G., Xu, Y., Zhang, Y., & Xiao, J. (2021). Percutaneous Intracoronary Delivery of Plasma Extracellular Vesicles Protects the Myocardium against Ischemia-Reperfusion Injury in Canis. Hypertension, 78(5), 1541-1554. https://doi.org/10.1161/HYPERTENSIONAHA.121.17574

@article{1ea6d85ff9694cb2bff12005d50e8786,

title = "Percutaneous Intracoronary Delivery of Plasma Extracellular Vesicles Protects the Myocardium against Ischemia-Reperfusion Injury in Canis",

abstract = "Plasma circulating extracellular vesicles (EVs) have been utilized as a potential therapeutic strategy to treat ischemic disease through intramyocardial injection (efficient but invasive) or tail vein injection (noninvasive but low cardiac retention). An effective and noninvasive delivery of EVs for future clinical use is necessary. The large animal (canine) model was complemented with a murine ischemia-reperfusion injury (IRI) model, as well as H9 human embryonic stem cell-induced cardiomyocytes or neonatal rat cardiomyocytes to investigate the effective delivery method and the role of plasma EVs in the IRI model. We further determine the crucial molecule within EVs that confers the cardioprotective role in vivo and in vitro and investigate the efficiency of CHP (cardiac homing peptide)-linked EVs in alleviating IRI. D-SPECT imaging showed that percutaneous intracoronary delivery of EVs reduced infarct extent in dogs. CHP-EVs further reduced IRI-induced cardiomyocyte apoptosis in mice and neonatal rat cardiomyocytes. Mechanistically, administration of EVs by percutaneous intracoronary delivery (in dog) and myocardial injection (in mice) just before reperfusion reduced infarct size of IRI by increasing miR-486 levels. miR-486-deleted EVs exacerbated oxygen-glucose deprivation/reoxygenation-induced human embryonic stem cell-induced cardiomyocytes and neonatal rat cardiomyocyte apoptosis. EV-miR-486 inhibited the PTEN (phosphatase and tensin homolog deleted on chromosome ten) expression and then promoted AKT (protein kinase B) activation in human embryonic stem cell-induced cardiomyocytes and neonatal rat cardiomyocytes. In conclusion, plasma-derived EVs convey miR-486 to the myocardium and attenuated IRI-induced infarction and cardiomyocyte apoptosis. CHP strategy was effective to improve cardiac retention of EVs in mice (in vivo) and dogs (ex vivo).",

keywords = "extracellular vesicles, infarction, microRNA, plasma, reperfusion injury",

author = "Hongyun Wang and Rusitanmujiang Maimaitiaili and Jianhua Yao and Yuling Xie and Sujing Qiang and Fan Hu and Xiang Li and Chao Shi and Peng Jia and Haotian Yang and Meng Wei and Juan Zhao and Zheng Zhou and Jinxin Xie and Jizong Jiang and Haidong Cai and Sluijter, {Joost P.G.} and Yawei Xu and Yi Zhang and Junjie Xiao",

note = "Publisher Copyright: {\textcopyright} 2021 American Heart Association, Inc.",

year = "2021",

month = nov,

doi = "10.1161/HYPERTENSIONAHA.121.17574",

language = "English",

volume = "78",

pages = "1541--1554",

journal = "Hypertension",

issn = "0194-911X",

publisher = "Lippincott Williams & Wilkins",

number = "5",

}

Wang, H, Maimaitiaili, R, Yao, J, Xie, Y, Qiang, S, Hu, F, Li, X, Shi, C, Jia, P, Yang, H, Wei, M, Zhao, J, Zhou, Z, Xie, J, Jiang, J, Cai, H, Sluijter, JPG, Xu, Y, Zhang, Y & Xiao, J 2021, 'Percutaneous Intracoronary Delivery of Plasma Extracellular Vesicles Protects the Myocardium against Ischemia-Reperfusion Injury in Canis', Hypertension, vol. 78, no. 5, pp. 1541-1554. https://doi.org/10.1161/HYPERTENSIONAHA.121.17574

TY - JOUR

T1 - Percutaneous Intracoronary Delivery of Plasma Extracellular Vesicles Protects the Myocardium against Ischemia-Reperfusion Injury in Canis

AU - Wang, Hongyun

AU - Maimaitiaili, Rusitanmujiang

AU - Yao, Jianhua

AU - Xie, Yuling

AU - Qiang, Sujing

AU - Hu, Fan

AU - Li, Xiang

AU - Shi, Chao

AU - Jia, Peng

AU - Yang, Haotian

AU - Wei, Meng

AU - Zhao, Juan

AU - Zhou, Zheng

AU - Xie, Jinxin

AU - Jiang, Jizong

AU - Cai, Haidong

AU - Sluijter, Joost P.G.

AU - Xu, Yawei

AU - Zhang, Yi

AU - Xiao, Junjie

PY - 2021/11

Y1 - 2021/11

N2 - Plasma circulating extracellular vesicles (EVs) have been utilized as a potential therapeutic strategy to treat ischemic disease through intramyocardial injection (efficient but invasive) or tail vein injection (noninvasive but low cardiac retention). An effective and noninvasive delivery of EVs for future clinical use is necessary. The large animal (canine) model was complemented with a murine ischemia-reperfusion injury (IRI) model, as well as H9 human embryonic stem cell-induced cardiomyocytes or neonatal rat cardiomyocytes to investigate the effective delivery method and the role of plasma EVs in the IRI model. We further determine the crucial molecule within EVs that confers the cardioprotective role in vivo and in vitro and investigate the efficiency of CHP (cardiac homing peptide)-linked EVs in alleviating IRI. D-SPECT imaging showed that percutaneous intracoronary delivery of EVs reduced infarct extent in dogs. CHP-EVs further reduced IRI-induced cardiomyocyte apoptosis in mice and neonatal rat cardiomyocytes. Mechanistically, administration of EVs by percutaneous intracoronary delivery (in dog) and myocardial injection (in mice) just before reperfusion reduced infarct size of IRI by increasing miR-486 levels. miR-486-deleted EVs exacerbated oxygen-glucose deprivation/reoxygenation-induced human embryonic stem cell-induced cardiomyocytes and neonatal rat cardiomyocyte apoptosis. EV-miR-486 inhibited the PTEN (phosphatase and tensin homolog deleted on chromosome ten) expression and then promoted AKT (protein kinase B) activation in human embryonic stem cell-induced cardiomyocytes and neonatal rat cardiomyocytes. In conclusion, plasma-derived EVs convey miR-486 to the myocardium and attenuated IRI-induced infarction and cardiomyocyte apoptosis. CHP strategy was effective to improve cardiac retention of EVs in mice (in vivo) and dogs (ex vivo).

AB - Plasma circulating extracellular vesicles (EVs) have been utilized as a potential therapeutic strategy to treat ischemic disease through intramyocardial injection (efficient but invasive) or tail vein injection (noninvasive but low cardiac retention). An effective and noninvasive delivery of EVs for future clinical use is necessary. The large animal (canine) model was complemented with a murine ischemia-reperfusion injury (IRI) model, as well as H9 human embryonic stem cell-induced cardiomyocytes or neonatal rat cardiomyocytes to investigate the effective delivery method and the role of plasma EVs in the IRI model. We further determine the crucial molecule within EVs that confers the cardioprotective role in vivo and in vitro and investigate the efficiency of CHP (cardiac homing peptide)-linked EVs in alleviating IRI. D-SPECT imaging showed that percutaneous intracoronary delivery of EVs reduced infarct extent in dogs. CHP-EVs further reduced IRI-induced cardiomyocyte apoptosis in mice and neonatal rat cardiomyocytes. Mechanistically, administration of EVs by percutaneous intracoronary delivery (in dog) and myocardial injection (in mice) just before reperfusion reduced infarct size of IRI by increasing miR-486 levels. miR-486-deleted EVs exacerbated oxygen-glucose deprivation/reoxygenation-induced human embryonic stem cell-induced cardiomyocytes and neonatal rat cardiomyocyte apoptosis. EV-miR-486 inhibited the PTEN (phosphatase and tensin homolog deleted on chromosome ten) expression and then promoted AKT (protein kinase B) activation in human embryonic stem cell-induced cardiomyocytes and neonatal rat cardiomyocytes. In conclusion, plasma-derived EVs convey miR-486 to the myocardium and attenuated IRI-induced infarction and cardiomyocyte apoptosis. CHP strategy was effective to improve cardiac retention of EVs in mice (in vivo) and dogs (ex vivo).

KW - extracellular vesicles

KW - infarction

KW - microRNA

KW - plasma

KW - reperfusion injury

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U2 - 10.1161/HYPERTENSIONAHA.121.17574

DO - 10.1161/HYPERTENSIONAHA.121.17574

M3 - Article

C2 - 34488435

AN - SCOPUS:85117362780

SN - 0194-911X

VL - 78

SP - 1541

EP - 1554

JO - Hypertension

JF - Hypertension

IS - 5

ER -

Percutaneous Intracoronary Delivery of Plasma Extracellular Vesicles Protects the Myocardium against Ischemia-Reperfusion Injury in Canis

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