MKP1, VSMC, and Vascular Remodeling

MKP1、VSMC 和血管重塑

基本信息

批准号：
10206241
负责人：
Ping Song
金额：
$ 68.77万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2021-12-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206241
关键词：
A549 Ablation Aorta Arterial Fatty Streak Atherosclerosis Attenuated Carotid Arteries Carotid Artery Injuries Cell Proliferation Cell-Free System Cells Complex DUSP1 gene Data Development Down-Regulation Etiology Exhibits Expenditure Gene Silencing Genes Goals Human Hyperplasia Impairment Injury Knowledge Liver Mediating Messenger RNA Mitogen-Activated Protein Kinases Modeling Molecular Mus Pathway interactions Patients Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Play Protein Biosynthesis Protein Kinase Proteins Regulation Research Resolution Role STAT protein STAT1 protein STK11 gene Smooth Muscle Myocytes Stenosis Testing Thrombus Up-Regulation Vascular Diseases Vascular Smooth Muscle Vascular remodeling cell motility cell type in vivo loss of function migration mouse model multicatalytic endopeptidase complex overexpression phosphatase-1 kinase prevent response restenosis upstream kinase vascular injury vascular smooth muscle cell proliferation wound healing

项目摘要

Abstract Overwhelming evidence from previous studies suggests that vascular smooth muscle cells (VSMCs) plays a critical role in development of neointima hyperplasia and atherosclerosis but exact molecular mechanisms are poorly understood. We have obtained exciting preliminary data suggesting that down-regulation of mitogen-activated protein kinase phosphatase-1 (MKP-1) protein levels is associated with increased cell proliferation and stenosis in patients with atherosclerosis. Similarly, MKP-1 protein levels and neointimal hyperplasia are decreased in a mouse model of wire-mediated carotid artery injury. MKP-1 is known to suppress activation of signal transducer and activator of transcription (STAT1) signaling, a critical step leading to VSMC proliferation and neointimal hyperplasia. More importantly, MKP-1 overexpression is associated with decreased human aortic smooth muscle cell (HASMC) proliferation, STAT1 phosphorylation, and neointimal hyperplasia formation in response to vascular injury. With a concomitant reduction in MKP-1 expression, both liver kinase (LKB)1 activity and LKB1 phosphorylation at Ser428 is decreased in the carotid artery after wire-mediated injury. Further, LKB1 directly phosphorylates MKP-1 in a cell-free system, and overexpression of constitutively active LKB1 in LKB1-deficient A549 cells inhibits MKP-1 degradation. Finally, VSMC-specific LKB1 deletion mice exhibit lower levels of MKP-1 in mouse aortas and exacerbated neointimal hyperplasia and atherosclerosis. Thus we hypothesize that LKB1-regulated MKP-1 suppresses VSMC proliferation, migration, neointimal formation, and atherosclerosis through the inhibition of STAT1 signaling. The goals of the present application are to characterize the mechanism by which LKB1 via MKP-1 suppresses VSMC proliferation, intimal hyperplasia, atherosclerosis, and determine whether the effect of MKP-1 is mediated through the inhibition of STAT1 signaling, which has been shown to promote VSMC proliferation and intimal hyperplasia (1) and impair thrombus resolution (2) and wound healing (3). Defining the roles of LKB1 in the regulation of VSMC proliferation, intimal hyperplasia, and atherosclerosis may identify potential targets for the treatment of atherothrombotic vascular diseases.

抽象的先前研究的压倒性证据表明，血管平滑肌细胞（VSMC）在新内膜增生和动脉粥样硬化的发展中起着关键作用，但确切的分子机制尚不清楚。我们获得了令人兴奋的初步数据表明丝裂原激活蛋白激酶磷酸酶-1 (MKP-1) 的下调蛋白质水平与患者的细胞增殖和狭窄增加有关动脉粥样硬化。同样，MKP-1 蛋白水平和新内膜增生在线介导的颈动脉损伤的小鼠模型。已知 MKP-1 可以抑制信号转导子和转录激活子 (STAT1) 信号转导，这是导致 VSMC 增殖和新内膜增生。更重要的是，MKP-1 过度表达是与人主动脉平滑肌细胞 (HASMC) 增殖减少相关，STAT1 磷酸化和响应血管损伤的新内膜增生形成。与一个 MKP-1 表达、肝激酶 (LKB)1 活性和 LKB1 的表达同时减少导线介导的损伤后，颈动脉中 Ser428 的磷酸化降低。更远， LKB1 在无细胞系统中直接磷酸化 MKP-1，并组成型过表达 LKB1 缺陷的 A549 细胞中活跃的 LKB1 抑制 MKP-1 降解。最后，VSMC特定 LKB1 缺失小鼠的主动脉中 MKP-1 水平较低，新生内膜加剧增生和动脉粥样硬化。因此我们假设 LKB1 调节 MKP-1 抑制 VSMC 增殖、迁移、新内膜形成和动脉粥样硬化通过抑制 STAT1 信号传导。本申请的目标是描述 LKB1 通过 MKP-1 抑制 VSMC 增殖、内膜增生、动脉粥样硬化，并确定 MKP-1 的作用是否是通过介导的 STAT1 信号传导的抑制，已被证明可以促进 VSMC 增殖和内膜增生 (1) 并损害血栓溶解 (2) 和伤口愈合 (3)。定义 LKB1在调节VSMC增殖、内膜增生和动脉粥样硬化中的作用可以确定治疗动脉粥样硬化血栓性血管疾病的潜在靶标。