Department of Medicine, University of Colorado at Denver-Anschutz Medical Campus, Aurora, CO, USA.
Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):733-41. doi: 10.1161/ATVBAHA.109.199133. Epub 2010 Feb 11.
To examine the impact of low-density lipoprotein (LDL), an established mediator of atherosclerosis, on the transcription factor cAMP-response element-binding protein (CREB), which is a regulator of vascular smooth muscle cell (VSMC) quiescence.
VSMC CREB content is diminished in rodent models of diabetes and pulmonary hypertension. We examined aortic CREB content in rodent models of aging, hypertension, and insulin resistance, and we determined nuclear CREB protein in the medial VSMC of high-fat-fed LDL receptor-null mice. There was significant loss of CREB protein in all models. In vitro, primary culture rat aortic VSMC exposed to LDL and oxidized LDL exhibited a rapid, transient increase in CREB phosphorylation and transient phosphorylation/activation of Akt, ERK, JNK, ans p38 MAPK. Exposure to oxidized LDL, but not to LDL, for 24 to 48 hours decreased CREB protein in a dose-dependent fashion and led to nuclear exclusion of CREB. Pharmacological reactive oxygen species scavengers and inhibition of ERK activation blocked oxidized LDL-mediated CREB downregulation.
These data support a model wherein loss of VSMC CREB protein, which renders these cells more susceptible to activation and apoptosis, is a common pathological response to vascular injury and potentially contributes to plaque progression.
研究低密度脂蛋白（LDL）作为动脉粥样硬化的一种已确立的介质，对血管平滑肌细胞（VSMC）静止的调节因子 cAMP 反应元件结合蛋白（CREB）的转录因子的影响。
糖尿病和肺动脉高压的啮齿动物模型中，VSMC CREB 含量减少。我们检测了衰老、高血压和胰岛素抵抗的啮齿动物模型中的主动脉 CREB 含量，并测定了高脂肪喂养的 LDL 受体缺失小鼠中中层 VSMC 的核 CREB 蛋白。在所有模型中，均存在 CREB 蛋白的显著丢失。在体外，原代培养的大鼠主动脉 VSMC 暴露于 LDL 和氧化 LDL 后，迅速、短暂地增加了 CREB 的磷酸化，以及 Akt、ERK、JNK 和 p38 MAPK 的短暂磷酸化/激活。暴露于氧化 LDL 而非 LDL 24 至 48 小时，以剂量依赖性方式降低 CREB 蛋白，并导致 CREB 核排除。药理学活性氧清除剂和 ERK 激活抑制阻断了氧化 LDL 介导的 CREB 下调。
这些数据支持这样一种模型，即 VSMC CREB 蛋白的丢失使这些细胞更容易被激活和凋亡，这是血管损伤的一种常见病理反应，并可能导致斑块进展。
