Gorenne I, Jin L, Yoshida T, Sanders J M, Sarembock I J, Owens G K, Somlyo A P, Somlyo A V
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
Circ Res. 2006 Feb 17;98(3):378-85. doi: 10.1161/01.RES.0000202802.34727.fd. Epub 2006 Jan 5.
Lipoma preferred partner (LPP) has been identified as a protein highly expressed in smooth muscle (SM) tissues. The aim of the present study was to determine mechanisms that regulate LPP expression in an in vitro model of SM cell (SMC) differentiation and in stent-induced pig coronary vessel injury. All trans-retinoic acid treatment of A404 cells induced a strong increase in LPP, as well as SM alpha-actin, SM myosin heavy chain, and smoothelin mRNA levels, in a Rho kinase (ROK)-dependent manner. Adenovirus mediated overexpression of myocardin in A404 cells significantly increased LPP mRNA expression. Interestingly, inactivation of RhoA with C3-exoenzyme or treatment with ROK inhibitors strongly inhibited myocardin mRNA expression in retinoic acid-treated A404 cells or human iliac vein SMCs. LPP silencing with short interfering RNA significantly decreased SMC migration. LPP expression was also markedly decreased in focal adhesion kinase (FAK)-null cells known to have impaired migration but rescued with inducible expression of FAK. LPP expression in FAK-null fibroblasts enhanced cell spreading. In stented pig coronary vessels, LPP was expressed in the neointima of cells lacking smoothelin and showed expression patterns identical to those of SM alpha-actin. In conclusion, LPP appears to be a myocardin-, RhoA/ROK-dependent SMC differentiation marker that plays a role in regulating SMC migration.
脂肪瘤优先伴侣蛋白（LPP）已被鉴定为一种在平滑肌（SM）组织中高表达的蛋白质。本研究的目的是确定在平滑肌细胞（SMC）分化的体外模型以及支架诱导的猪冠状动脉损伤中调节LPP表达的机制。全反式维甲酸处理A404细胞以一种依赖于Rho激酶（ROK）的方式强烈增加了LPP以及平滑肌α-肌动蛋白、平滑肌肌球蛋白重链和平滑肌肌动蛋白mRNA的水平。腺病毒介导的心肌素在A404细胞中的过表达显著增加了LPP mRNA的表达。有趣的是，用C3外切酶使RhoA失活或用ROK抑制剂处理可强烈抑制维甲酸处理的A404细胞或人髂静脉SMC中心肌素mRNA的表达。用小干扰RNA沉默LPP可显著降低SMC的迁移。在已知迁移受损但通过诱导性表达黏着斑激酶（FAK）得以挽救的FAK基因敲除细胞中，LPP的表达也明显降低。FAK基因敲除的成纤维细胞中LPP的表达增强了细胞铺展。在置入支架的猪冠状动脉血管中，LPP在缺乏平滑肌肌动蛋白的内膜细胞中表达，并且显示出与平滑肌α-肌动蛋白相同的表达模式。总之，LPP似乎是一种依赖于心肌素、RhoA/ROK的SMC分化标志物，在调节SMC迁移中发挥作用。
