Reducing In-Stent Restenosis: Therapeutic Manipulation of miRNA in Vascular Remodeling and Inflammation

Robert A. McDonald; Crawford A. Halliday; Ashley M. Miller; Louise A. Diver; Rachel S. Dakin; Jennifer Montgomery; Martin W. McBride; Simon Kennedy; John D. McClure; Keith E. Robertson; Gillian Douglas; Keith M. Channon; Keith G. Oldroyd; Andrew H. Baker

doi:10.1016/j.jacc.2015.03.549

Reducing In-Stent Restenosis: Therapeutic Manipulation of miRNA in Vascular Remodeling and Inflammation

Robert A. McDonald, Crawford A. Halliday, Ashley M. Miller, Louise A. Diver, Rachel S. Dakin, Jennifer Montgomery, Martin W. McBride, Simon Kennedy, John D. McClure, Keith E. Robertson, Gillian Douglas, Keith M. Channon, Keith G. Oldroyd, Andrew H. Baker

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

Abstract

BACKGROUND: Drug-eluting stents reduce the incidence of in-stent restenosis, but they result in delayed arterial healing and are associated with a chronic inflammatory response and hypersensitivity reactions. Identifying novel interventions to enhance wound healing and reduce the inflammatory response may improve long-term clinical outcomes. Micro-ribonucleic acids (miRNAs) are noncoding small ribonucleic acids that play a prominent role in the initiation and resolution of inflammation after vascular injury.

OBJECTIVES: This study sought to identify miRNA regulation and function after implantation of bare-metal and drug-eluting stents.

METHODS: Pig, mouse, and in vitro models were used to investigate the role of miRNA in in-stent restenosis.

RESULTS: We documented a subset of inflammatory miRNAs activated after stenting in pigs, including the miR-21 stem loop miRNAs. Genetic ablation of the miR-21 stem loop attenuated neointimal formation in mice post-stenting. This occurred via enhanced levels of anti-inflammatory M2 macrophages coupled with an impaired sensitivity of smooth muscle cells to respond to vascular activation.

CONCLUSIONS: MiR-21 plays a prominent role in promoting vascular inflammation and remodeling after stent injury. MiRNA-mediated modulation of the inflammatory response post-stenting may have therapeutic potential to accelerate wound healing and enhance the clinical efficacy of stenting.

Original language	English
Pages (from-to)	2314-2327
Number of pages	14
Journal	Journal of the American College of Cardiology
Volume	65
Issue number	21
Early online date	25 May 2015
DOIs	https://doi.org/10.1016/j.jacc.2015.03.549
Publication status	Published - 2 Jun 2015

Keywords / Materials (for Non-textual outputs)

Animals
Coronary Restenosis
Drug-Eluting Stents
Inflammation
Male
Mice, Knockout
MicroRNAs
Swine
Vascular Remodeling
Vascular System Injuries
late stent thrombosis
miRNA stem loop
neointima
smooth muscle cell

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10.1016/j.jacc.2015.03.549Licence: Creative Commons: Attribution (CC-BY)

Andrew Baker
- Andy.Bakered.acuk
- andy.bakered.acuk
- Deanery of Clinical Sciences - Gustav Born Chair of Vascular Biology
- Centre for Cardiovascular Science
Person: Academic: Research Active

Cite this

McDonald, R. A., Halliday, C. A., Miller, A. M., Diver, L. A., Dakin, R. S., Montgomery, J., McBride, M. W., Kennedy, S., McClure, J. D., Robertson, K. E., Douglas, G., Channon, K. M., Oldroyd, K. G., & Baker, A. H. (2015). Reducing In-Stent Restenosis: Therapeutic Manipulation of miRNA in Vascular Remodeling and Inflammation. Journal of the American College of Cardiology, 65(21), 2314-2327. https://doi.org/10.1016/j.jacc.2015.03.549

@article{a1d0a8ac96e34b5a9a5a7982479dd33e,

title = "Reducing In-Stent Restenosis: Therapeutic Manipulation of miRNA in Vascular Remodeling and Inflammation",

abstract = "BACKGROUND: Drug-eluting stents reduce the incidence of in-stent restenosis, but they result in delayed arterial healing and are associated with a chronic inflammatory response and hypersensitivity reactions. Identifying novel interventions to enhance wound healing and reduce the inflammatory response may improve long-term clinical outcomes. Micro-ribonucleic acids (miRNAs) are noncoding small ribonucleic acids that play a prominent role in the initiation and resolution of inflammation after vascular injury.OBJECTIVES: This study sought to identify miRNA regulation and function after implantation of bare-metal and drug-eluting stents.METHODS: Pig, mouse, and in vitro models were used to investigate the role of miRNA in in-stent restenosis.RESULTS: We documented a subset of inflammatory miRNAs activated after stenting in pigs, including the miR-21 stem loop miRNAs. Genetic ablation of the miR-21 stem loop attenuated neointimal formation in mice post-stenting. This occurred via enhanced levels of anti-inflammatory M2 macrophages coupled with an impaired sensitivity of smooth muscle cells to respond to vascular activation.CONCLUSIONS: MiR-21 plays a prominent role in promoting vascular inflammation and remodeling after stent injury. MiRNA-mediated modulation of the inflammatory response post-stenting may have therapeutic potential to accelerate wound healing and enhance the clinical efficacy of stenting.",

keywords = "Animals, Coronary Restenosis, Drug-Eluting Stents, Inflammation, Male, Mice, Knockout, MicroRNAs, Swine, Vascular Remodeling, Vascular System Injuries, late stent thrombosis, miRNA stem loop, neointima, smooth muscle cell",

author = "McDonald, {Robert A.} and Halliday, {Crawford A.} and Miller, {Ashley M.} and Diver, {Louise A.} and Dakin, {Rachel S.} and Jennifer Montgomery and McBride, {Martin W.} and Simon Kennedy and McClure, {John D.} and Robertson, {Keith E.} and Gillian Douglas and Channon, {Keith M.} and Oldroyd, {Keith G.} and Baker, {Andrew H.}",

note = " (J Am Coll Cardiol 2015;65:2314–27) {\textcopyright} 2015 The Authors. Published by Elsevier Inc. on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).",

year = "2015",

month = jun,

day = "2",

doi = "10.1016/j.jacc.2015.03.549",

language = "English",

volume = "65",

pages = "2314--2327",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier Inc.",

number = "21",

}

McDonald, RA, Halliday, CA, Miller, AM, Diver, LA, Dakin, RS, Montgomery, J, McBride, MW, Kennedy, S, McClure, JD, Robertson, KE, Douglas, G, Channon, KM, Oldroyd, KG & Baker, AH 2015, 'Reducing In-Stent Restenosis: Therapeutic Manipulation of miRNA in Vascular Remodeling and Inflammation', Journal of the American College of Cardiology, vol. 65, no. 21, pp. 2314-2327. https://doi.org/10.1016/j.jacc.2015.03.549

TY - JOUR

T1 - Reducing In-Stent Restenosis: Therapeutic Manipulation of miRNA in Vascular Remodeling and Inflammation

AU - McDonald, Robert A.

AU - Halliday, Crawford A.

AU - Miller, Ashley M.

AU - Diver, Louise A.

AU - Dakin, Rachel S.

AU - Montgomery, Jennifer

AU - McBride, Martin W.

AU - Kennedy, Simon

AU - McClure, John D.

AU - Robertson, Keith E.

AU - Douglas, Gillian

AU - Channon, Keith M.

AU - Oldroyd, Keith G.

AU - Baker, Andrew H.

N1 - (J Am Coll Cardiol 2015;65:2314–27) © 2015 The Authors. Published by Elsevier Inc. on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PY - 2015/6/2

Y1 - 2015/6/2

N2 - BACKGROUND: Drug-eluting stents reduce the incidence of in-stent restenosis, but they result in delayed arterial healing and are associated with a chronic inflammatory response and hypersensitivity reactions. Identifying novel interventions to enhance wound healing and reduce the inflammatory response may improve long-term clinical outcomes. Micro-ribonucleic acids (miRNAs) are noncoding small ribonucleic acids that play a prominent role in the initiation and resolution of inflammation after vascular injury.OBJECTIVES: This study sought to identify miRNA regulation and function after implantation of bare-metal and drug-eluting stents.METHODS: Pig, mouse, and in vitro models were used to investigate the role of miRNA in in-stent restenosis.RESULTS: We documented a subset of inflammatory miRNAs activated after stenting in pigs, including the miR-21 stem loop miRNAs. Genetic ablation of the miR-21 stem loop attenuated neointimal formation in mice post-stenting. This occurred via enhanced levels of anti-inflammatory M2 macrophages coupled with an impaired sensitivity of smooth muscle cells to respond to vascular activation.CONCLUSIONS: MiR-21 plays a prominent role in promoting vascular inflammation and remodeling after stent injury. MiRNA-mediated modulation of the inflammatory response post-stenting may have therapeutic potential to accelerate wound healing and enhance the clinical efficacy of stenting.

AB - BACKGROUND: Drug-eluting stents reduce the incidence of in-stent restenosis, but they result in delayed arterial healing and are associated with a chronic inflammatory response and hypersensitivity reactions. Identifying novel interventions to enhance wound healing and reduce the inflammatory response may improve long-term clinical outcomes. Micro-ribonucleic acids (miRNAs) are noncoding small ribonucleic acids that play a prominent role in the initiation and resolution of inflammation after vascular injury.OBJECTIVES: This study sought to identify miRNA regulation and function after implantation of bare-metal and drug-eluting stents.METHODS: Pig, mouse, and in vitro models were used to investigate the role of miRNA in in-stent restenosis.RESULTS: We documented a subset of inflammatory miRNAs activated after stenting in pigs, including the miR-21 stem loop miRNAs. Genetic ablation of the miR-21 stem loop attenuated neointimal formation in mice post-stenting. This occurred via enhanced levels of anti-inflammatory M2 macrophages coupled with an impaired sensitivity of smooth muscle cells to respond to vascular activation.CONCLUSIONS: MiR-21 plays a prominent role in promoting vascular inflammation and remodeling after stent injury. MiRNA-mediated modulation of the inflammatory response post-stenting may have therapeutic potential to accelerate wound healing and enhance the clinical efficacy of stenting.

KW - Animals

KW - Coronary Restenosis

KW - Drug-Eluting Stents

KW - Inflammation

KW - Male

KW - Mice, Knockout

KW - MicroRNAs

KW - Swine

KW - Vascular Remodeling

KW - Vascular System Injuries

KW - late stent thrombosis

KW - miRNA stem loop

KW - neointima

KW - smooth muscle cell

U2 - 10.1016/j.jacc.2015.03.549

DO - 10.1016/j.jacc.2015.03.549

M3 - Article

C2 - 26022821

SN - 0735-1097

VL - 65

SP - 2314

EP - 2327

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 21

ER -

Reducing In-Stent Restenosis: Therapeutic Manipulation of miRNA in Vascular Remodeling and Inflammation

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