PEA‐15 (Phosphoprotein Enriched in Astrocytes 15) Is a Protective Mediator in the Vasculature and Is Regulated During Neointimal Hyperplasia

Fiona H Greig, Simon Kennedy, George Gibson, Joe W Ramos, Graeme F Nixon

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Abstract

Background: Neointimal hyperplasia following angioplasty occurs via vascular smooth muscle cell proliferation. The mechanisms involved are not fully understood but include mitogen‐activated protein kinases ERK1/2 (extracellular signal–regulated kinases 1 and 2). We recently identified the intracellular mediator PEA‐15 (phosphoprotein enriched in astrocytes 15) in vascular smooth muscle cells as a regulator of ERK1/2‐dependent proliferation in vitro. PEA‐15 acts as a cytoplasmic anchor for ERK1/2, preventing nuclear localization and thereby reducing ERK1/2‐dependent gene expression. The aim of the current study was to examine the role of PEA‐15 in neointimal hyperplasia in vivo.

Method and Results: Mice deficient in PEA‐15 or wild‐type mice were subjected to wire injury of the carotid artery. In uninjured arteries from PEA‐15–deficient mice, ERK1/2 had increased nuclear translocation and increased basal ERK1/2‐dependent transcription. Following wire injury, arteries from PEA‐15–deficient mice developed neointimal hyperplasia at an increased rate compared with wild‐type mice. This occurred in parallel with an increase in a proliferative marker and vascular smooth muscle cell proliferation. In wild‐type mice, PEA‐15 expression was decreased in vascular smooth muscle cells at an early stage before any increase in intima:media ratio. This regulation of PEA‐15 expression following injury was also observed in an ex vivo human model of hyperplasia.

Conclusions: These results indicate, for the first time, a novel protective role for PEA‐15 against inappropriate vascular proliferation. PEA‐15 expression may also be repressed during vascular injury, suggesting that maintenance of PEA‐15 expression is a novel therapeutic target in vascular disease.
Original languageEnglish
Article numbere006936
Pages (from-to)1-15
Number of pages15
JournalJournal of the American Heart Association
Volume6
Issue number9
DOIs
Publication statusPublished - 11 Sep 2017

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Phosphoproteins
Astrocytes
Hyperplasia
Vascular Smooth Muscle
Smooth Muscle Myocytes
Phosphotransferases
Arteries
Cell Proliferation
Carotid Artery Injuries
Vascular System Injuries
Wounds and Injuries
Vascular Diseases
Angioplasty
Protein Kinases
Blood Vessels
Maintenance
Gene Expression

Keywords

  • neointimal hyperplasia
  • vascular smooth muscle
  • proliferation
  • mitogen-activated protein kinase pathway

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PEA‐15 (Phosphoprotein Enriched in Astrocytes 15) Is a Protective Mediator in the Vasculature and Is Regulated During Neointimal Hyperplasia. / Greig, Fiona H; Kennedy, Simon; Gibson, George; Ramos, Joe W; Nixon, Graeme F.

In: Journal of the American Heart Association, Vol. 6, No. 9, e006936, 11.09.2017, p. 1-15.

Research output: Contribution to journalArticle

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title = "PEA‐15 (Phosphoprotein Enriched in Astrocytes 15) Is a Protective Mediator in the Vasculature and Is Regulated During Neointimal Hyperplasia",
abstract = "Background: Neointimal hyperplasia following angioplasty occurs via vascular smooth muscle cell proliferation. The mechanisms involved are not fully understood but include mitogen‐activated protein kinases ERK1/2 (extracellular signal–regulated kinases 1 and 2). We recently identified the intracellular mediator PEA‐15 (phosphoprotein enriched in astrocytes 15) in vascular smooth muscle cells as a regulator of ERK1/2‐dependent proliferation in vitro. PEA‐15 acts as a cytoplasmic anchor for ERK1/2, preventing nuclear localization and thereby reducing ERK1/2‐dependent gene expression. The aim of the current study was to examine the role of PEA‐15 in neointimal hyperplasia in vivo.Method and Results: Mice deficient in PEA‐15 or wild‐type mice were subjected to wire injury of the carotid artery. In uninjured arteries from PEA‐15–deficient mice, ERK1/2 had increased nuclear translocation and increased basal ERK1/2‐dependent transcription. Following wire injury, arteries from PEA‐15–deficient mice developed neointimal hyperplasia at an increased rate compared with wild‐type mice. This occurred in parallel with an increase in a proliferative marker and vascular smooth muscle cell proliferation. In wild‐type mice, PEA‐15 expression was decreased in vascular smooth muscle cells at an early stage before any increase in intima:media ratio. This regulation of PEA‐15 expression following injury was also observed in an ex vivo human model of hyperplasia.Conclusions: These results indicate, for the first time, a novel protective role for PEA‐15 against inappropriate vascular proliferation. PEA‐15 expression may also be repressed during vascular injury, suggesting that maintenance of PEA‐15 expression is a novel therapeutic target in vascular disease.",
keywords = "neointimal hyperplasia, vascular smooth muscle, proliferation, mitogen-activated protein kinase pathway",
author = "Greig, {Fiona H} and Simon Kennedy and George Gibson and Ramos, {Joe W} and Nixon, {Graeme F}",
note = "This work was supported by a grant from the Medical Research Council, UK (MR/K012789/1).",
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AU - Gibson, George

AU - Ramos, Joe W

AU - Nixon, Graeme F

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N2 - Background: Neointimal hyperplasia following angioplasty occurs via vascular smooth muscle cell proliferation. The mechanisms involved are not fully understood but include mitogen‐activated protein kinases ERK1/2 (extracellular signal–regulated kinases 1 and 2). We recently identified the intracellular mediator PEA‐15 (phosphoprotein enriched in astrocytes 15) in vascular smooth muscle cells as a regulator of ERK1/2‐dependent proliferation in vitro. PEA‐15 acts as a cytoplasmic anchor for ERK1/2, preventing nuclear localization and thereby reducing ERK1/2‐dependent gene expression. The aim of the current study was to examine the role of PEA‐15 in neointimal hyperplasia in vivo.Method and Results: Mice deficient in PEA‐15 or wild‐type mice were subjected to wire injury of the carotid artery. In uninjured arteries from PEA‐15–deficient mice, ERK1/2 had increased nuclear translocation and increased basal ERK1/2‐dependent transcription. Following wire injury, arteries from PEA‐15–deficient mice developed neointimal hyperplasia at an increased rate compared with wild‐type mice. This occurred in parallel with an increase in a proliferative marker and vascular smooth muscle cell proliferation. In wild‐type mice, PEA‐15 expression was decreased in vascular smooth muscle cells at an early stage before any increase in intima:media ratio. This regulation of PEA‐15 expression following injury was also observed in an ex vivo human model of hyperplasia.Conclusions: These results indicate, for the first time, a novel protective role for PEA‐15 against inappropriate vascular proliferation. PEA‐15 expression may also be repressed during vascular injury, suggesting that maintenance of PEA‐15 expression is a novel therapeutic target in vascular disease.

AB - Background: Neointimal hyperplasia following angioplasty occurs via vascular smooth muscle cell proliferation. The mechanisms involved are not fully understood but include mitogen‐activated protein kinases ERK1/2 (extracellular signal–regulated kinases 1 and 2). We recently identified the intracellular mediator PEA‐15 (phosphoprotein enriched in astrocytes 15) in vascular smooth muscle cells as a regulator of ERK1/2‐dependent proliferation in vitro. PEA‐15 acts as a cytoplasmic anchor for ERK1/2, preventing nuclear localization and thereby reducing ERK1/2‐dependent gene expression. The aim of the current study was to examine the role of PEA‐15 in neointimal hyperplasia in vivo.Method and Results: Mice deficient in PEA‐15 or wild‐type mice were subjected to wire injury of the carotid artery. In uninjured arteries from PEA‐15–deficient mice, ERK1/2 had increased nuclear translocation and increased basal ERK1/2‐dependent transcription. Following wire injury, arteries from PEA‐15–deficient mice developed neointimal hyperplasia at an increased rate compared with wild‐type mice. This occurred in parallel with an increase in a proliferative marker and vascular smooth muscle cell proliferation. In wild‐type mice, PEA‐15 expression was decreased in vascular smooth muscle cells at an early stage before any increase in intima:media ratio. This regulation of PEA‐15 expression following injury was also observed in an ex vivo human model of hyperplasia.Conclusions: These results indicate, for the first time, a novel protective role for PEA‐15 against inappropriate vascular proliferation. PEA‐15 expression may also be repressed during vascular injury, suggesting that maintenance of PEA‐15 expression is a novel therapeutic target in vascular disease.

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