Smooth muscle enriched long noncoding RNA (SMILR) regulates cell proliferation

Margaret D. Ballantyne, Karine Pinel, Rachel Dakin, Alex T. Vesey, Louise Diver, Ruth Mackenzie, Raquel Garcia, Paul Welsh, Naveed Sattar, Graham Hamilton, Nikhil Joshi, Marc R. Dweck, Joseph M. Miano, Martin W. McBride, David E. Newby, Robert A. McDonald, Andrew H. Baker

Research output: Contribution to journalArticle

Abstract

Background - Phenotypic switching of vascular smooth muscle cells from a contractile to a synthetic state is implicated in diverse vascular pathologies, including atherogenesis, plaque stabilization, and neointimal hyperplasia. However, very little is known about the role of long noncoding RNA (lncRNA) during this process. Here, we investigated a role for lncRNAs in vascular smooth muscle cell biology and pathology. Methods and Results - Using RNA sequencing, we identified >300 lncRNAs whose expression was altered in human saphenous vein vascular smooth muscle cells following stimulation with interleukin-1α and platelet-derived growth factor. We focused on a novel lncRNA (Ensembl: RP11-94A24.1), which we termed smooth muscle-induced lncRNA enhances replication (SMILR). Following stimulation, SMILR expression was increased in both the nucleus and cytoplasm, and was detected in conditioned media. Furthermore, knockdown of SMILR markedly reduced cell proliferation. Mechanistically, we noted that expression of genes proximal to SMILR was also altered by interleukin-1α/platelet-derived growth factor treatment, and HAS2 expression was reduced by SMILR knockdown. In human samples, we observed increased expression of SMILR in unstable atherosclerotic plaques and detected increased levels in plasma from patients with high plasma C-reactive protein. Conclusions - These results identify SMILR as a driver of vascular smooth muscle cell proliferation and suggest that modulation of SMILR may be a novel therapeutic strategy to reduce vascular pathologies.

Original languageEnglish (US)
Pages (from-to)2050-2065
Number of pages16
JournalCirculation
Volume133
Issue number21
DOIs
StatePublished - May 24 2016

Fingerprint

Long Noncoding RNA
Smooth Muscle
Cell Proliferation
Vascular Smooth Muscle
Smooth Muscle Myocytes
Platelet-Derived Growth Factor
Pathology
Interleukin-1
Blood Vessels
RNA Sequence Analysis
Saphenous Vein
Atherosclerotic Plaques
Conditioned Culture Medium
C-Reactive Protein
Hyperplasia
Cell Biology

Keywords

  • RNA, untranslated
  • atherosclerosis
  • cell proliferation
  • microRNAs
  • plasma protein, human

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Ballantyne, M. D., Pinel, K., Dakin, R., Vesey, A. T., Diver, L., Mackenzie, R., ... Baker, A. H. (2016). Smooth muscle enriched long noncoding RNA (SMILR) regulates cell proliferation. Circulation, 133(21), 2050-2065. https://doi.org/10.1161/CIRCULATIONAHA.115.021019

Smooth muscle enriched long noncoding RNA (SMILR) regulates cell proliferation. / Ballantyne, Margaret D.; Pinel, Karine; Dakin, Rachel; Vesey, Alex T.; Diver, Louise; Mackenzie, Ruth; Garcia, Raquel; Welsh, Paul; Sattar, Naveed; Hamilton, Graham; Joshi, Nikhil; Dweck, Marc R.; Miano, Joseph M.; McBride, Martin W.; Newby, David E.; McDonald, Robert A.; Baker, Andrew H.

In: Circulation, Vol. 133, No. 21, 24.05.2016, p. 2050-2065.

Research output: Contribution to journalArticle

Ballantyne, MD, Pinel, K, Dakin, R, Vesey, AT, Diver, L, Mackenzie, R, Garcia, R, Welsh, P, Sattar, N, Hamilton, G, Joshi, N, Dweck, MR, Miano, JM, McBride, MW, Newby, DE, McDonald, RA & Baker, AH 2016, 'Smooth muscle enriched long noncoding RNA (SMILR) regulates cell proliferation', Circulation, vol. 133, no. 21, pp. 2050-2065. https://doi.org/10.1161/CIRCULATIONAHA.115.021019
Ballantyne MD, Pinel K, Dakin R, Vesey AT, Diver L, Mackenzie R et al. Smooth muscle enriched long noncoding RNA (SMILR) regulates cell proliferation. Circulation. 2016 May 24;133(21):2050-2065. https://doi.org/10.1161/CIRCULATIONAHA.115.021019
Ballantyne, Margaret D. ; Pinel, Karine ; Dakin, Rachel ; Vesey, Alex T. ; Diver, Louise ; Mackenzie, Ruth ; Garcia, Raquel ; Welsh, Paul ; Sattar, Naveed ; Hamilton, Graham ; Joshi, Nikhil ; Dweck, Marc R. ; Miano, Joseph M. ; McBride, Martin W. ; Newby, David E. ; McDonald, Robert A. ; Baker, Andrew H. / Smooth muscle enriched long noncoding RNA (SMILR) regulates cell proliferation. In: Circulation. 2016 ; Vol. 133, No. 21. pp. 2050-2065.
@article{bfe36d6ac1fd4198b9fa0a7fe83982f6,
title = "Smooth muscle enriched long noncoding RNA (SMILR) regulates cell proliferation",
abstract = "Background - Phenotypic switching of vascular smooth muscle cells from a contractile to a synthetic state is implicated in diverse vascular pathologies, including atherogenesis, plaque stabilization, and neointimal hyperplasia. However, very little is known about the role of long noncoding RNA (lncRNA) during this process. Here, we investigated a role for lncRNAs in vascular smooth muscle cell biology and pathology. Methods and Results - Using RNA sequencing, we identified >300 lncRNAs whose expression was altered in human saphenous vein vascular smooth muscle cells following stimulation with interleukin-1α and platelet-derived growth factor. We focused on a novel lncRNA (Ensembl: RP11-94A24.1), which we termed smooth muscle-induced lncRNA enhances replication (SMILR). Following stimulation, SMILR expression was increased in both the nucleus and cytoplasm, and was detected in conditioned media. Furthermore, knockdown of SMILR markedly reduced cell proliferation. Mechanistically, we noted that expression of genes proximal to SMILR was also altered by interleukin-1α/platelet-derived growth factor treatment, and HAS2 expression was reduced by SMILR knockdown. In human samples, we observed increased expression of SMILR in unstable atherosclerotic plaques and detected increased levels in plasma from patients with high plasma C-reactive protein. Conclusions - These results identify SMILR as a driver of vascular smooth muscle cell proliferation and suggest that modulation of SMILR may be a novel therapeutic strategy to reduce vascular pathologies.",
keywords = "RNA, untranslated, atherosclerosis, cell proliferation, microRNAs, plasma protein, human",
author = "Ballantyne, {Margaret D.} and Karine Pinel and Rachel Dakin and Vesey, {Alex T.} and Louise Diver and Ruth Mackenzie and Raquel Garcia and Paul Welsh and Naveed Sattar and Graham Hamilton and Nikhil Joshi and Dweck, {Marc R.} and Miano, {Joseph M.} and McBride, {Martin W.} and Newby, {David E.} and McDonald, {Robert A.} and Baker, {Andrew H.}",
year = "2016",
month = "5",
day = "24",
doi = "10.1161/CIRCULATIONAHA.115.021019",
language = "English (US)",
volume = "133",
pages = "2050--2065",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "21",

}

TY - JOUR

T1 - Smooth muscle enriched long noncoding RNA (SMILR) regulates cell proliferation

AU - Ballantyne, Margaret D.

AU - Pinel, Karine

AU - Dakin, Rachel

AU - Vesey, Alex T.

AU - Diver, Louise

AU - Mackenzie, Ruth

AU - Garcia, Raquel

AU - Welsh, Paul

AU - Sattar, Naveed

AU - Hamilton, Graham

AU - Joshi, Nikhil

AU - Dweck, Marc R.

AU - Miano, Joseph M.

AU - McBride, Martin W.

AU - Newby, David E.

AU - McDonald, Robert A.

AU - Baker, Andrew H.

PY - 2016/5/24

Y1 - 2016/5/24

N2 - Background - Phenotypic switching of vascular smooth muscle cells from a contractile to a synthetic state is implicated in diverse vascular pathologies, including atherogenesis, plaque stabilization, and neointimal hyperplasia. However, very little is known about the role of long noncoding RNA (lncRNA) during this process. Here, we investigated a role for lncRNAs in vascular smooth muscle cell biology and pathology. Methods and Results - Using RNA sequencing, we identified >300 lncRNAs whose expression was altered in human saphenous vein vascular smooth muscle cells following stimulation with interleukin-1α and platelet-derived growth factor. We focused on a novel lncRNA (Ensembl: RP11-94A24.1), which we termed smooth muscle-induced lncRNA enhances replication (SMILR). Following stimulation, SMILR expression was increased in both the nucleus and cytoplasm, and was detected in conditioned media. Furthermore, knockdown of SMILR markedly reduced cell proliferation. Mechanistically, we noted that expression of genes proximal to SMILR was also altered by interleukin-1α/platelet-derived growth factor treatment, and HAS2 expression was reduced by SMILR knockdown. In human samples, we observed increased expression of SMILR in unstable atherosclerotic plaques and detected increased levels in plasma from patients with high plasma C-reactive protein. Conclusions - These results identify SMILR as a driver of vascular smooth muscle cell proliferation and suggest that modulation of SMILR may be a novel therapeutic strategy to reduce vascular pathologies.

AB - Background - Phenotypic switching of vascular smooth muscle cells from a contractile to a synthetic state is implicated in diverse vascular pathologies, including atherogenesis, plaque stabilization, and neointimal hyperplasia. However, very little is known about the role of long noncoding RNA (lncRNA) during this process. Here, we investigated a role for lncRNAs in vascular smooth muscle cell biology and pathology. Methods and Results - Using RNA sequencing, we identified >300 lncRNAs whose expression was altered in human saphenous vein vascular smooth muscle cells following stimulation with interleukin-1α and platelet-derived growth factor. We focused on a novel lncRNA (Ensembl: RP11-94A24.1), which we termed smooth muscle-induced lncRNA enhances replication (SMILR). Following stimulation, SMILR expression was increased in both the nucleus and cytoplasm, and was detected in conditioned media. Furthermore, knockdown of SMILR markedly reduced cell proliferation. Mechanistically, we noted that expression of genes proximal to SMILR was also altered by interleukin-1α/platelet-derived growth factor treatment, and HAS2 expression was reduced by SMILR knockdown. In human samples, we observed increased expression of SMILR in unstable atherosclerotic plaques and detected increased levels in plasma from patients with high plasma C-reactive protein. Conclusions - These results identify SMILR as a driver of vascular smooth muscle cell proliferation and suggest that modulation of SMILR may be a novel therapeutic strategy to reduce vascular pathologies.

KW - RNA, untranslated

KW - atherosclerosis

KW - cell proliferation

KW - microRNAs

KW - plasma protein, human

UR - http://www.scopus.com/inward/record.url?scp=84963649305&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84963649305&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.115.021019

DO - 10.1161/CIRCULATIONAHA.115.021019

M3 - Article

C2 - 27052414

AN - SCOPUS:84963649305

VL - 133

SP - 2050

EP - 2065

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 21

ER -