Role of zyxin family members in hypertension-induced arterial remodelling

zyxin家族成员在高血压引起的动脉重塑中的作用

• 批准号: 329853703
• 负责人: Professor Dr. Markus Hecker, Ph.D.
• 金额: --
• 依托单位: Institut für Physiologie und Pathophysiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/329853703?language=en
• 关键词: Role; zyxin; family; members; hypertension

Chronic arterial hypertension increases wall tension in both large conduit and small resistance-sized arteries. Continuous stretch, especially of the vascular smooth muscle cells (VSMC), leads to maladaptive remodelling of the vessel wall (hypertrophy in the former and hyperplasia in the latter type of arteries) including reorganization of the extracellular matrix, stiffening the conduit arteries and increasing peripheral resistance. The manifested arterial hypertension overloads the heart, especially the left ventricle, with the risk of cardiac hypertrophy and possibly cardiac insufficiency. Work of our group shows that in highly stretched endothelial cells (EC) and VSMC zyxin, a protein localized in focal adhesions, translocates to the nucleus where it controls expression of 70% and 90% of the mechanosensitive genes, respectively. In EC it acts as a mechanoresponsive transcription factor, in VSMC it changes actin dynamics and the RhoA-MRTF-A signalling pathway. VSMC isolated from the aorta of 3 months old global zyxin knockout mice show an activated synthetic phenotype. In vivo, these mice develop a phenotype only when hypertension is experimentally induced at the age of 6-18 months. The cardiac phenotype, which is comparable to restrictive cardiomyopathy in humans, can already be seen in young animals. The vascular phenotype, which corresponds to that of VSMC from zyxin-deficient mice in vitro, solely occurs in the oldest group and is only weakly developed. Recent studies suggest that this is not due to the loss of zyxin but to an age-dependent decline of its close relative, lipoma preferred partner (LPP), the overexpression of which reverses cultured zyxin-null VSMC into the dormant contractile phenotype. VSMC isolated from the aorta of global LPP knockout mice show an activated synthetic phenotype, whereas LPP knockout mice in vivo, in contrast to zyxin knockout mice, do not show a cardiac phenotype in any phase of life, but a pronounced vascular phenotype, especially in 12-month old animals. The latter manifests itself only in the face of experimental hypertension primarily in the descending aorta and, in the middle third of the 21-day observation period, resembles an exacerbated Marfan syndrome with a highly unstable vessel wall. Since LPP, unlike zyxin, is not expressed in the endothelium of both conduit and resistance-sized arteries from wild-type mice, the renewal application focuses on the role of LPP in the VSMC in the context of hypertension-induced maladaptive remodelling as follows: (1) Verification of the vascular phenotype of the global LPP knockout mice in the already generated tamoxifen-inducible VSMC-specific LPP knockout mice. (2) Characterization of the underlying cellular and molecular mechanisms with a focus on reduced contractility in the smaller and destabilization of the extracellular matrix in the larger arteries, respectively. (3) Confirmation of the putative phenotype-stabilising role of LPP in human VSMC.

慢性动脉高血压增加了大导管和小阻力动脉的壁张力。持续的拉伸，尤其是血管平滑肌细胞（VSMC）的拉伸，会导致血管壁的不适应重构（前者动脉肥大，后者动脉增生），包括细胞外基质的重组、导管动脉硬化和外周阻力的增加。明显的动脉高血压使心脏，特别是左心室负荷过重，有心肌肥厚和可能的心功能不全的危险。我们小组的工作表明，在高度拉伸的内皮细胞（EC）和VSMC中，zyxin，一种定位于局灶粘连的蛋白质，易位到细胞核，在那里它分别控制70%和90%的机械敏感基因的表达。在EC中，它作为一种机械反应性转录因子，在VSMC中，它改变肌动蛋白动力学和RhoA-MRTF-A信号通路。从3月龄全球zyxin敲除小鼠主动脉分离的VSMC显示出活化的合成表型。在体内，这些小鼠只有在6-18个月大时实验性诱导高血压时才会出现这种表型。与人类的限制性心肌病相当的心脏表型，已经可以在年轻的动物身上看到。血管表型与体外zyxin缺陷小鼠的VSMC相对应，仅发生在年龄最大的组中，且发育较弱。最近的研究表明，这不是由于zyxin的损失，而是由于其近亲脂肪瘤首选伴侣（LPP）的年龄依赖性下降，LPP的过表达将培养的zyxin-null VSMC逆转为休眠收缩表型。从LPP基因敲除小鼠主动脉分离的VSMC显示出活化的合成表型，而LPP基因敲除小鼠在体内，与zyxin基因敲除小鼠相比，在生命的任何阶段都没有显示出心脏表型，但明显的血管表型，特别是在12个月大的动物中。后者仅表现为主要发生在降主动脉的实验性高血压，在21天观察期的中间三分之一，类似于血管壁高度不稳定的加重马凡氏综合征。由于LPP与zyxin不同，在野生型小鼠的导管和阻力动脉内皮中均不表达，因此更新应用的重点是LPP在高血压诱导的不适应重构背景下在VSMC中的作用：(1)在已经产生的他莫昔芬诱导的VSMC特异性LPP敲除小鼠中验证全球LPP敲除小鼠的血管表型。(2)描述了潜在的细胞和分子机制，重点关注了大动脉中较小的细胞外基质的收缩性降低和不稳定。(3)证实了LPP在人类VSMC中的表型稳定作用。