Unspliced XBP1 Confers VSMC Homeostasis and Prevents Aortic Aneurysm Formation via FoxO4 Interaction
Unspliced XBP1 Confers VSMC Homeostasis and Prevents Aortic Aneurysm Formation via FoxO4 Interaction
复制标题
未拼接的 XBP1 通过 FoxO4 相互作用赋予 VSMC 稳态并防止主动脉瘤形成。
DOI：
10.1161/circresaha.117.311450
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发表时间：
2017-12-08
影响因子：
20.1
通讯作者：
Kong, Wei
中科院分区：
文献类型：
--
作者：
Zhao, Guizhen;Fu, Yi;Kong, Wei
基本原理：虽然尚未完全了解，但血管平滑肌细胞的表型转变在主动脉瘤病理学的早期发作时表现出来。探索负责维持血管平滑肌细胞（VSMCs）收缩表型的关键调节因子可能赋予血管稳态并预防血管平滑肌疾病。XBP 1（X-box binding protein 1，X-box binding protein 1）是内质网应激反应中的一个重要组成部分，以非转录活性的非剪接形式（XBP 1u）和剪接活性形式（XBP 1 s）存在。与XBP 1 s相比，人们对XBP 1u在血管稳态和疾病中的作用知之甚少。目的：我们的目的是探讨XBP 1u在VSMC表型转换和主动脉瘤发病机制中的作用。方法和结果：XBP 1u，但不是XBP 1 s，在血管紧张素II注入载脂蛋白E基因敲除的两种情况下，（ApoE（-/-））和CaPO 4（磷酸钙）诱导的C57 BL/6 J小鼠模型，与平滑肌细胞收缩装置蛋白的减少平行。体内研究表明，平滑肌细胞中的XBP 1缺陷导致VSMC去分化，增强血管炎症和蛋白水解活性，并显著加重小鼠胸主动脉瘤和腹主动脉瘤。XBP 1缺陷，但不是XBP 1剪接的抑制，诱导VSMC从收缩表型转变为促炎症和蛋白水解表型。在细胞质中，XBP 1u通过与myocardin的相互作用和抑制作用，直接与FoxO 4（Forkhead box protein O 4）的N端结合，FoxO 4是一种公认的VSMC分化抑制因子。阻断XBP 1u-FoxO 4相互作用促进FoxO 4的核转位，抑制平滑肌细胞标记基因的表达，促进促炎和蛋白水解表型转换在体外，并刺激主动脉瘤形成在vivo.Conclusions：我们的研究揭示了关键作用的XBP 1u-FoxO 4-myocardin轴在维持VSMC收缩表型和提供保护，从主动脉瘤形成。
Rationale: Although not fully understood, the phenotypic transition of vascular smooth muscle cells exhibits at the early onset of the pathology of aortic aneurysms. Exploring the key regulators that are responsible for maintaining the contractile phenotype of vascular smooth muscle cells (VSMCs) may confer vascular homeostasis and prevent aneurysmal disease. XBP1 (X-box binding protein 1), which exists in a transcriptionally inactive unspliced form (XBP1u) and a spliced active form (XBP1s), is a key component in response to endoplasmic reticular stress. Compared with XBP1s, little is known about the role of XBP1u in vascular homeostasis and disease.Objective: We aim to investigate the role of XBP1u in VSMC phenotypic switching and the pathogenesis of aortic aneurysms.Methods and Results: XBP1u, but not XBP1s, was markedly repressed in the aorta during the early onset of aortic aneurysm in both angiotensin II-infused apolipoprotein E knockout (ApoE(-/-)) and CaPO4 (calcium phosphate)induced C57BL/6J murine models, in parallel with a decrease in smooth muscle cell contractile apparatus proteins. In vivo studies revealed that XBP1 deficiency in smooth muscle cells caused VSMC dedifferentiation, enhanced vascular inflammation and proteolytic activity, and significantly aggravated both thoracic and abdominal aortic aneurysms in mice. XBP1 deficiency, but not an inhibition of XBP1 splicing, induced VSMC switching from the contractile phenotype to a proinflammatory and proteolytic phenotype. Mechanically, in the cytoplasm, XBP1u directly associated with the N terminus of FoxO4 (Forkhead box protein O 4), a recognized repressor of VSMC differentiation via the interaction and inhibition of myocardin. Blocking the XBP1u-FoxO4 interaction facilitated nuclear translocation of FoxO4, repressed smooth muscle cell marker genes expression, promoted proinflammatory and proteolytic phenotypic transitioning in vitro, and stimulated aortic aneurysm formation in vivo.Conclusions: Our study revealed the pivotal role of the XBP1u-FoxO4-myocardin axis in maintaining the VSMC contractile phenotype and providing protection from aortic aneurysm formation.