MKP1, VSMC, and Vascular Remodeling

MKP1、VSMC 和血管重塑

• 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
• 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

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.

摘要 先前研究的压倒性证据表明，血管平滑肌细胞 血管平滑肌细胞（VSMCs）在新生内膜增生和动脉粥样硬化的发展中起关键作用， 确切的分子机制知之甚少。我们获得了令人振奋的初步数据 提示丝裂原活化蛋白激酶磷酸酶-1（MKP-1）的下调 蛋白质水平与患者的细胞增殖和狭窄增加相关， 动脉粥样硬化同样，MKP-1蛋白水平和新生内膜增生减少， 导丝介导的颈动脉损伤的小鼠模型。已知MKP-1可抑制 信号转导子和转录激活子（STAT 1）信号传导，这是导致 VSMC增殖和新生内膜增生。更重要的是，MKP-1过表达是 与人主动脉平滑肌细胞（HASMC）增殖减少相关，STAT 1 磷酸化和响应血管损伤的新生内膜增生形成。与 伴随MKP-1表达降低，肝激酶（LKB）1活性和LKB 1 在金属丝介导的损伤后，颈动脉中Ser 428的磷酸化降低。此外，本发明还 LKB 1在无细胞系统中直接磷酸化MKP-1，并且组成性过度表达MKP-1。 LKB 1缺陷型A549细胞中的活性LKB 1抑制MKP-1降解。最后，特定于VSMC LKB 1缺失小鼠在小鼠动脉粥样硬化中表现出较低的MKP-1水平，并加剧了新生内膜增生。 增生和动脉粥样硬化。因此，我们假设LKB 1调节的MKP-1 抑制VSMC增殖、迁移、新生内膜形成和动脉粥样硬化 通过抑制STAT 1信号传导。本申请的目的是 描述了LKB 1通过MKP-1抑制VSMC增殖、内膜增生和血管生成的机制。 增生，动脉粥样硬化，并确定MKP-1的作用是否通过介导 STAT 1信号传导的抑制，其已显示促进VSMC增殖， 内膜增生（1）和损害血栓消退（2）和伤口愈合（3）。定义 LKB 1在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点。