Laboratory of Molecular and Genetic Cardiovascular Pathophysiology, Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
Arterioscler Thromb Vasc Biol. 2011 Nov;31(11):2455-63. doi: 10.1161/ATVBAHA.111.235580.
Genetic ablation of the growth suppressor p27(Kip1) (p27) in the mouse aggravates atherosclerosis coinciding with enhanced arterial cell proliferation. However, it is unknown whether molecular mechanisms that limit p27's protective function contribute to atherosclerosis development and whether p27 exerts proliferation-independent activities in the arterial wall. This study aims to provide insight into both questions by investigating the role in atherosclerosis of p27 phosphorylation at serine 10 (p27-phospho-Ser10), a major posttranslational modification of this protein.
Immunoblotting studies revealed a marked reduction in p27-phospho-Ser10 in atherosclerotic arteries from apolipoprotein E-null mice, and expression of the nonphosphorylatable mutant p27Ser10Ala, either global or restricted to bone marrow, accelerated atherosclerosis. p27Ser10Ala expression did not affect cell proliferation in early and advanced atheroma but activated RhoA/Rho-associated coiled-coil containing protein kinase (ROCK) signaling and promoted macrophage foam cell formation in a ROCK-dependent manner. Supporting the clinical relevance of these findings, human atherosclerotic coronary arteries exhibited a prominent reduction in p27-phospho-Ser10 and increased ezrin/radixin/moesin protein phosphorylation, a marker of RhoA/ROCK activation.
Scarce phosphorylation of p27 at Ser10 is a hallmark of human and mouse atherosclerosis and promotes disease progression in mice. This proatherogenic effect is mediated by a proliferation-independent mechanism that involves augmented foam cell formation owing to increased RhoA/ROCK activity. These findings unveil a new atheroprotective action of p27 and identify p27-phospho-Ser10 as an attractive target for the treatment of atherosclerosis.
生长抑制因子 p27（Kip1）（p27）在小鼠中的基因缺失会加剧动脉粥样硬化，同时伴随着动脉细胞增殖增强。然而，目前尚不清楚限制 p27 保护功能的分子机制是否会导致动脉粥样硬化的发生，以及 p27 是否在动脉壁中发挥增殖非依赖性的作用。本研究旨在通过研究该蛋白的主要翻译后修饰之一丝氨酸 10 磷酸化（p27-phospho-Ser10）在动脉粥样硬化中的作用，来深入了解这两个问题。
免疫印迹研究显示，载脂蛋白 E 基因敲除小鼠的动脉粥样硬化病变中 p27-phospho-Ser10 明显减少，而全身性或仅限于骨髓的非磷酸化突变 p27Ser10Ala 的表达则加速了动脉粥样硬化的发生。p27Ser10Ala 的表达并不影响早期和晚期动脉粥样硬化中的细胞增殖，但能激活 RhoA/Rho 相关卷曲螺旋蛋白激酶（ROCK）信号通路，并以 ROCK 依赖的方式促进巨噬细胞泡沫细胞的形成。这些发现与临床相关性一致，人类动脉粥样硬化性冠状动脉中 p27-phospho-Ser10 的减少以及 ezrin/radixin/moesin 蛋白磷酸化的增加，提示 RhoA/ROCK 的激活。
p27 在丝氨酸 10 上的低磷酸化是人类和小鼠动脉粥样硬化的一个标志，并促进了小鼠的疾病进展。这种促动脉粥样硬化的作用是通过一种增殖非依赖性的机制介导的，该机制涉及由于 RhoA/ROCK 活性增加而导致的泡沫细胞形成增加。这些发现揭示了 p27 的一种新的抗动脉粥样硬化作用，并将 p27-phospho-Ser10 确定为动脉粥样硬化治疗的一个有吸引力的靶点。
