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.

慢性动脉高血压会增加大管和小电阻大小的动脉的壁张力。连续拉伸，尤其是血管平滑肌细胞（VSMC），导致血管壁（前者的肥大和后一种动脉的增生）导致适应不良的重塑，包括细胞外基质的重新组织，从而僵化了旋转动脉和增加外周的耐受性。表现出的动脉高血压超负荷是心脏，尤其是左心室，患有心脏肥大和可能的心脏不足的风险。我们小组的工作表明，在高度拉伸的内皮细胞（EC）和VSMC Zyxin中，一种局部局部粘附的蛋白质，分别易位到核，分别控制着70％和90％的机械敏感基因的表达。在EC中，它充当机械响应转录因子，在VSMC中它改变了肌动蛋白动力学和RhoA-MRTF-A信号通路。从3个月大的全球Zyxin敲除小鼠的主动脉中分离出的VSMC显示出激活的合成表型。在体内，这些小鼠只有在6-18个月大的实验诱导高血压时才会形成表型。在年轻动物中已经可以看到与人类的限制性心肌病相媲美的心脏表型。血管表型与缺乏Zyxin缺陷小鼠的VSMC相对应，仅发生在最古老的组中，并且仅发育较弱。最近的研究表明，这并不是由于Zyxin的丧失，而是由于其近亲，脂肪瘤首选伴侣（LPP）的年龄依赖性下降，后表达逆转了培养的Zyxin-Null VSMC，使其转化为休眠的收缩表型。从全球LPP敲除小鼠主动脉分离的VSMC显示出激活的合成表型，而与Zyxin敲除小鼠相比，体内LPP敲除小鼠在生命的任何阶段都没有显示出心脏表型，而是一种明显的血管表型，尤其是在12个小时的动物中，尤其是在12个小时的动物中。后者仅在实验性高血压的面前表现出来，主要是在下降主动脉中，在21天观察期的中间，类似于一个加重的Marfan综合征，具有高度不稳定的容器壁。由于LPP与Zyxin不同，在导管和电阻大小的动脉的内皮中未表达来自野生型小鼠的动脉，因此更新的应用集中在LPP在VSMC中的作用，在高血压诱发的不良疾病引起的重塑的背景下如下所示：（1）探讨了已探讨全球LPP的探测。他莫昔芬可诱导的VSMC特异性LPP敲除小鼠。 （2）表征下面的细胞和分子机制，重点是分别降低较大动脉的细胞外基质的收缩力降低。 （3）确认LPP在人VSMC中的假定表型稳定作用。