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

Research output: Contribution to journalArticle

2 Citations (Scopus)
6 Downloads (Pure)

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

Keywords

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

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