Inhibition of miR-92a improves re-endothelialization and prevents neointima formation following vascular injury

Jan-Marcus Daniel; Daniela Penzkofer; Rebecca Teske; Jochen Dutzmann; Alexander Koch; Wiebke Bielenberg; Angelika Bonauer; Reinier A Boon; Ariane Fischer; Johann Bauersachs; Eva van Rooij; Stefanie Dimmeler; Daniel G Sedding

doi:10.1093/cvr/cvu162

Inhibition of miR-92a improves re-endothelialization and prevents neointima formation following vascular injury

Jan-Marcus Daniel, Daniela Penzkofer, Rebecca Teske, Jochen Dutzmann, Alexander Koch, Wiebke Bielenberg, Angelika Bonauer, Reinier A Boon, Ariane Fischer, Johann Bauersachs, Eva van Rooij, Stefanie Dimmeler, Daniel G Sedding

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

119 Citations (Scopus)

Abstract

AIMS: MicroRNA (miR)-92a is an important regulator of endothelial proliferation and angiogenesis after ischaemia, but the effects of miR-92a on re-endothelialization and neointimal lesion formation after vascular injury remain elusive. We tested the effects of lowering miR-92a levels using specific locked nucleic acid (LNA)-based antimiRs as well as endothelial-specific knock out of miR-92a on re-endothelialization and neointimal formation after wire-induced injury of the femoral artery in mice.

METHODS AND RESULTS: MiR-92a was significantly up-regulated in neointimal lesions following wire-induced injury. Pre-miR-92a overexpression resulted in repression of the direct miR-92a target genes integrin α5 and sirtuin1, and reduced eNOS expression in vitro. MiR-92a impaired proliferation and migration of endothelial cells but not smooth muscle cells. In vivo, systemic inhibition of miR-92a expression with LNA-modified antisense molecules resulted in a significant acceleration of re-endothelialization of the denuded vessel area. Genetic deletion of miR-92a in Tie2-expressing cells, representing mainly endothelial cells, enhanced re-endothelialization, whereas no phenotype was observed in mice lacking miR-92a expression in haematopoietic cells. The enhanced endothelial recovery was associated with reduced accumulation of leucocytes and inhibition of neointimal formation 21 days after injury and led to the de-repression of the miR-92a targets integrin α5 and sirtuin1.

CONCLUSION: Our data indicate that inhibition of endothelial miR-92a attenuates neointimal lesion formation by accelerating re-endothelialization and thus represents a putative novel mechanism to enhance the functional recovery following vascular injury.

Original language	English
Pages (from-to)	564-72
Number of pages	9
Journal	Cardiovascular Research
Volume	103
Issue number	4
DOIs	https://doi.org/10.1093/cvr/cvu162
Publication status	Published - 01 Sept 2014

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10.1093/cvr/cvu162

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Daniel, J.-M., Penzkofer, D., Teske, R., Dutzmann, J., Koch, A., Bielenberg, W., Bonauer, A., Boon, R. A., Fischer, A., Bauersachs, J., van Rooij, E., Dimmeler, S., & Sedding, D. G. (2014). Inhibition of miR-92a improves re-endothelialization and prevents neointima formation following vascular injury. Cardiovascular Research, 103(4), 564-72. https://doi.org/10.1093/cvr/cvu162

@article{ebe41b91ae6c44b69098439079abfe27,

title = "Inhibition of miR-92a improves re-endothelialization and prevents neointima formation following vascular injury",

abstract = "AIMS: MicroRNA (miR)-92a is an important regulator of endothelial proliferation and angiogenesis after ischaemia, but the effects of miR-92a on re-endothelialization and neointimal lesion formation after vascular injury remain elusive. We tested the effects of lowering miR-92a levels using specific locked nucleic acid (LNA)-based antimiRs as well as endothelial-specific knock out of miR-92a on re-endothelialization and neointimal formation after wire-induced injury of the femoral artery in mice.METHODS AND RESULTS: MiR-92a was significantly up-regulated in neointimal lesions following wire-induced injury. Pre-miR-92a overexpression resulted in repression of the direct miR-92a target genes integrin α5 and sirtuin1, and reduced eNOS expression in vitro. MiR-92a impaired proliferation and migration of endothelial cells but not smooth muscle cells. In vivo, systemic inhibition of miR-92a expression with LNA-modified antisense molecules resulted in a significant acceleration of re-endothelialization of the denuded vessel area. Genetic deletion of miR-92a in Tie2-expressing cells, representing mainly endothelial cells, enhanced re-endothelialization, whereas no phenotype was observed in mice lacking miR-92a expression in haematopoietic cells. The enhanced endothelial recovery was associated with reduced accumulation of leucocytes and inhibition of neointimal formation 21 days after injury and led to the de-repression of the miR-92a targets integrin α5 and sirtuin1.CONCLUSION: Our data indicate that inhibition of endothelial miR-92a attenuates neointimal lesion formation by accelerating re-endothelialization and thus represents a putative novel mechanism to enhance the functional recovery following vascular injury.",

author = "Jan-Marcus Daniel and Daniela Penzkofer and Rebecca Teske and Jochen Dutzmann and Alexander Koch and Wiebke Bielenberg and Angelika Bonauer and Boon, {Reinier A} and Ariane Fischer and Johann Bauersachs and {van Rooij}, Eva and Stefanie Dimmeler and Sedding, {Daniel G}",

note = "{\textcopyright} The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.",

year = "2014",

month = sep,

day = "1",

doi = "10.1093/cvr/cvu162",

language = "English",

volume = "103",

pages = "564--72",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

number = "4",

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Daniel, J-M, Penzkofer, D, Teske, R, Dutzmann, J, Koch, A, Bielenberg, W, Bonauer, A, Boon, RA, Fischer, A, Bauersachs, J, van Rooij, E, Dimmeler, S & Sedding, DG 2014, 'Inhibition of miR-92a improves re-endothelialization and prevents neointima formation following vascular injury', Cardiovascular Research, vol. 103, no. 4, pp. 564-72. https://doi.org/10.1093/cvr/cvu162

TY - JOUR

T1 - Inhibition of miR-92a improves re-endothelialization and prevents neointima formation following vascular injury

AU - Daniel, Jan-Marcus

AU - Penzkofer, Daniela

AU - Teske, Rebecca

AU - Dutzmann, Jochen

AU - Koch, Alexander

AU - Bielenberg, Wiebke

AU - Bonauer, Angelika

AU - Boon, Reinier A

AU - Fischer, Ariane

AU - Bauersachs, Johann

AU - van Rooij, Eva

AU - Dimmeler, Stefanie

AU - Sedding, Daniel G

PY - 2014/9/1

Y1 - 2014/9/1

N2 - AIMS: MicroRNA (miR)-92a is an important regulator of endothelial proliferation and angiogenesis after ischaemia, but the effects of miR-92a on re-endothelialization and neointimal lesion formation after vascular injury remain elusive. We tested the effects of lowering miR-92a levels using specific locked nucleic acid (LNA)-based antimiRs as well as endothelial-specific knock out of miR-92a on re-endothelialization and neointimal formation after wire-induced injury of the femoral artery in mice.METHODS AND RESULTS: MiR-92a was significantly up-regulated in neointimal lesions following wire-induced injury. Pre-miR-92a overexpression resulted in repression of the direct miR-92a target genes integrin α5 and sirtuin1, and reduced eNOS expression in vitro. MiR-92a impaired proliferation and migration of endothelial cells but not smooth muscle cells. In vivo, systemic inhibition of miR-92a expression with LNA-modified antisense molecules resulted in a significant acceleration of re-endothelialization of the denuded vessel area. Genetic deletion of miR-92a in Tie2-expressing cells, representing mainly endothelial cells, enhanced re-endothelialization, whereas no phenotype was observed in mice lacking miR-92a expression in haematopoietic cells. The enhanced endothelial recovery was associated with reduced accumulation of leucocytes and inhibition of neointimal formation 21 days after injury and led to the de-repression of the miR-92a targets integrin α5 and sirtuin1.CONCLUSION: Our data indicate that inhibition of endothelial miR-92a attenuates neointimal lesion formation by accelerating re-endothelialization and thus represents a putative novel mechanism to enhance the functional recovery following vascular injury.

AB - AIMS: MicroRNA (miR)-92a is an important regulator of endothelial proliferation and angiogenesis after ischaemia, but the effects of miR-92a on re-endothelialization and neointimal lesion formation after vascular injury remain elusive. We tested the effects of lowering miR-92a levels using specific locked nucleic acid (LNA)-based antimiRs as well as endothelial-specific knock out of miR-92a on re-endothelialization and neointimal formation after wire-induced injury of the femoral artery in mice.METHODS AND RESULTS: MiR-92a was significantly up-regulated in neointimal lesions following wire-induced injury. Pre-miR-92a overexpression resulted in repression of the direct miR-92a target genes integrin α5 and sirtuin1, and reduced eNOS expression in vitro. MiR-92a impaired proliferation and migration of endothelial cells but not smooth muscle cells. In vivo, systemic inhibition of miR-92a expression with LNA-modified antisense molecules resulted in a significant acceleration of re-endothelialization of the denuded vessel area. Genetic deletion of miR-92a in Tie2-expressing cells, representing mainly endothelial cells, enhanced re-endothelialization, whereas no phenotype was observed in mice lacking miR-92a expression in haematopoietic cells. The enhanced endothelial recovery was associated with reduced accumulation of leucocytes and inhibition of neointimal formation 21 days after injury and led to the de-repression of the miR-92a targets integrin α5 and sirtuin1.CONCLUSION: Our data indicate that inhibition of endothelial miR-92a attenuates neointimal lesion formation by accelerating re-endothelialization and thus represents a putative novel mechanism to enhance the functional recovery following vascular injury.

U2 - 10.1093/cvr/cvu162

DO - 10.1093/cvr/cvu162

M3 - Article

C2 - 25020912

SN - 0008-6363

VL - 103

SP - 564

EP - 572

JO - Cardiovascular Research

JF - Cardiovascular Research

IS - 4

ER -

Inhibition of miR-92a improves re-endothelialization and prevents neointima formation following vascular injury

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