上海交大最新PNAS文章

　　

　　在国家自然科学基金重点项目（11232010）、优秀青年科学基金项目（11222223）和面上项目（11572199）等的资助下，上海交通大学齐颖新、姜宗来教授团队在血管力学生物学研究方面取得新进展。有关细胞核骨架蛋白力学响应的研究成果以 “Nuclear Envelope Proteins Modulate Proliferation of Vascular Smooth Muscle Cells during Cyclic Stretch Application” 为题于2016年4月25 日在Proc Natl Acad Sci USA（美国科学院院刊）在线发表。

　　细胞如何将胞外的力学刺激信号转化为胞内的生物化学信号是细胞力信号转导（mechano-transduction）的关键科学问题。国内外现有的相关研究多数集中在细胞膜表面应力感受器方面，如膜蛋白和离子通道等。

    上海交通大学团队的研究关注了细胞核这一细胞内硬度（stiffness）最高和基因转录发生的亚细胞结构，以“动物整体水平观察现象－细胞分子水平探讨机制－动物整体水平验证发现” 的研究思路，探讨了细胞核骨架蛋白 emerin和 laminA/C 在高血压高张应变诱导血管平滑肌细胞（VSMCs）增殖中的作用及其机制，发现了emerin 和 laminA/C作为重要的保护性因子，其表达降低参与了高血压高张应变诱导的 VSMCs 异常增殖；揭示了emerin 和 laminA/C 可分别与包含特异性转录因子motif序列的DNA片段结合，进而调控多种与VSMCs增殖相关的转录因子活性。结果表明，核骨架蛋白能够响应张应变力学刺激，参与调控细胞功能，并提示核骨架蛋白 emerin 和 laminA/C有可能作为高血压血管重建的潜在靶标分子，具有重要的临床转化价值。

    这一研究成果将对机械应力感受器的关注由细胞表面转到细胞核，为细胞应力响应机制研究开辟了一个新方向，为发现新的细胞应力感受器、揭示应力诱导血管重建的分子机制与寻找血管重建临床诊断治疗和疗效评价的潜在靶点提供了力学生物学新的重要依据。

原文摘要：

Nuclear Envelope Proteins Modulate Proliferation of Vascular Smooth Muscle Cells during Cyclic Stretch Application

Cyclic stretch is an important inducer of vascular smooth muscle cell (VSMC) proliferation, which is crucial in vascular remodeling during hypertension. However, the molecular mechanism remains unclear. We studied the effects of emerin and lamin A/C, two important nuclear envelope proteins, on VSMC proliferation in hypertension and the underlying mechano-mechanisms. In common carotid artery of hypertensive rats in vivo and in cultured cells subjected to high (15%) cyclic stretch in vitro, VSMC proliferation was increased significantly, and the expression of emerin and lamin A/C was repressed compared with normotensive or normal (5%) cyclic stretch controls. Using targeted siRNA to mimic the repressed expression of emerin or lamin A/C induced by 15% stretch, we found that VSMC proliferation was enhanced under static and 5%-stretch conditions. Overexpression of emerin or lamin A/C reversed VSMC proliferation induced by 15% stretch. Hence, emerin and lamin A/C play critical roles in suppressing VSMC hyperproliferation induced by hyperstretch. ChIP-on-chip and MOTIF analyses showed that the DNAs binding with emerin contain three transcription factor motifs: CCNGGA, CCMGCC, and ABTTCCG; DNAs binding with lamin A/C contain the motifs CVGGAA, GCCGCYGC, and DAAGAAA. Protein/DNA array proved that altered emerin or lamin A/C expression modulated the activation of various transcription factors. Furthermore, accelerating local expression of emerin or lamin A/C reversed cell proliferation in the carotid artery of hypertensive rats in vivo. Our findings establish the pathogenetic role of emerin and lamin A/C repression in stretch-induced VSMC proliferation and suggest mechanobiological mechanism underlying this process that involves the sequence-specific binding of emerin and lamin A/C to specific transcription factor motifs.