Centre for Vascular Research, University of New South Wales, Sydney, NSW, 2052, Australia.
J Mol Med (Berl). 2010 Jun;88(6):545-52. doi: 10.1007/s00109-010-0615-4. Epub 2010 Mar 21.
Atherosclerosis is a complex fibroproliferative-inflammatory process triggered by vascular injury. Transcription factors play an important role in the control of genes that effect critical changes in the vessel wall. Recent evidence indicates an emerging role for activation transcription factor 4 (ATF4), a master regulator for evolutionarily conserved mammalian stress response pathways, in cardiovascular pathologic settings. For example, in endothelial cells, ATF4 is induced by atherogenic factors such as oxidised phospholipids and homocysteine, and in monocytes, ATF4 is activated by hypoxia. In this context, ATF4 is thought to regulate pro-inflammatory signalling cascades and subsequent apoptosis. ATF4 is induced in aortic smooth muscle cells by fibroblast growth factor 2 and in the intact vessel wall following balloon angioplasty. Our own work indicates that ATF4 knockdown blocks injury-inducible intimal proliferation. Furthermore, studies in ATF4-deficient mice have established a role for ATF4 in diet-induced diabetes and hyperlipidaemia. In this article, we will review recent developments on the regulation of this intriguing nuclear protein and its transcriptional roles in the context of vascular injury and related disease.
动脉粥样硬化是一种由血管损伤引发的复杂纤维增生性炎症过程。转录因子在控制对血管壁产生关键影响的基因方面发挥着重要作用。最近的证据表明，激活转录因子 4（ATF4）在心血管病理环境中具有新兴作用，ATF4 是进化上保守的哺乳动物应激反应途径的主要调节剂。例如，在血管内皮细胞中，ATF4 由动脉粥样硬化因子如氧化磷脂和同型半胱氨酸诱导，在单核细胞中，ATF4 由缺氧激活。在这种情况下，ATF4 被认为调节促炎信号级联反应和随后的细胞凋亡。成纤维细胞生长因子 2 可诱导主动脉平滑肌细胞中 ATF4 的产生，球囊血管成形术后完整血管壁中也可产生 ATF4。我们自己的工作表明，ATF4 敲低可阻止损伤诱导的内膜增殖。此外，在 ATF4 缺陷小鼠中的研究确立了 ATF4 在饮食诱导的糖尿病和高脂血症中的作用。在本文中，我们将回顾关于这种引人入胜的核蛋白的最新调控进展及其在血管损伤及相关疾病背景下的转录作用。
