School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, United Kingdom.
Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom.
J Am Heart Assoc. 2017 Sep 11;6(9):e006936. doi: 10.1161/JAHA.117.006936.
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.
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.
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.
血管成形术后的新生内膜增生是通过血管平滑肌细胞增殖发生的。涉及的机制尚未完全了解，但包括丝裂原活化蛋白激酶 ERK1/2（细胞外信号调节激酶 1 和 2）。我们最近在血管平滑肌细胞中鉴定了 PEA-15（富含星形胶质细胞的磷酸蛋白 15）作为细胞内介质，是体外 ERK1/2 依赖性增殖的调节剂。PEA-15 作为 ERK1/2 的细胞质锚定物，可防止核定位，从而减少 ERK1/2 依赖性基因表达。本研究的目的是研究 PEA-15 在体内新生内膜增生中的作用。
PEA-15 缺陷小鼠或野生型小鼠接受颈动脉线损伤。在 PEA-15 缺陷小鼠的未受伤动脉中，ERK1/2 核易位增加，ERK1/2 依赖性转录增加。在 wire 损伤后，与野生型小鼠相比，PEA-15 缺陷小鼠的动脉以更快的速度发展为新生内膜增生。这与增殖标志物和血管平滑肌细胞增殖的增加平行发生。在野生型小鼠中，在血管中层比率增加之前，PEA-15 表达在早期血管平滑肌细胞中减少。这种损伤后 PEA-15 表达的调节也在体外人增生模型中观察到。
这些结果首次表明 PEA-15 对血管过度增殖具有新颖的保护作用。PEA-15 的表达也可能在血管损伤后受到抑制，这表明维持 PEA-15 的表达是血管疾病的新治疗靶点。
