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Circ Res:北京大学孔炜教授团队发现非剪切型XBP-1抑制主动脉瘤发病新机制

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摘要 : 近日,国际心血管领域杂志《Circulation Research》在线发表了北京大学基础医学院生理与病理生理系孔炜教授课题组题为“Unspliced XBP1 Confers VSMCs Homeostasis and Prevents Aortic Aneurysm Formation via FoxO4 Interaction”的研究成果

近日,国际心血管领域杂志《Circulation Research》在线发表了北京大学基础医学院生理与病理生理系孔炜教授课题组题为“Unspliced XBP1 Confers VSMCs Homeostasis and Prevents Aortic Aneurysm Formation via FoxO4 Interaction”的研究成果,揭示了非剪切型XBP-1通过调控平滑肌细胞表型转化抑制主动脉瘤的作用机制。孔炜教授团队博士研究生赵桂珍为论文第一作者,孔炜教授为论文通讯作者。

主动脉瘤是一种异常凶险的心血管疾病,目前尚无有效的治疗药物,其发病机制不明。XBP1(X-box binding protein 1)是经典的内质网应激信号分子,存在剪接(spliced XBP1,XBP1s)和非剪接(unspliced XBP1,XBP1u)两种形式。孔炜教授课题组发现:XBP1u通过内质网应激非依赖的途径,抑制胸/腹主动脉瘤的发生。其具体机制是:XBP1u结合转录因子FoxO4,抑制FoxO4核转位,解除了FoxO4对平滑肌收缩元件的关键转录因子myocardin的转录抑制作用,从而维持血管平滑肌细胞的收缩稳态;如果阻断XBP1u-FoxO4的结合会促进血管平滑肌细胞由正常收缩表型向炎症和蛋白水解表型转化,并进而促进基质降解及主动脉瘤的发生。该研究揭示了血管平滑肌细胞的表型转化和主动脉瘤发生的连接分子,为寻找防治主动脉瘤的靶点提供了新的思路。

Circ Res:北京大学孔炜教授团队发现非剪切型XBP-1抑制主动脉瘤发病新机制
XBP1u-FoxO4-myocardin信号通路调控平滑肌细胞表型转化示意图

原文链接:

UnsplICEd XBP1 Confers VSMC Homeostasis and Prevents Aortic Aneurysm Formation via FoxO4 Interaction.

原文摘要:

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.

doi:10.1161/CIRCRESAHA.117.311450

作者:孔炜 点击:

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