Arterial Remodeling in Chronic Liver Diseases

慢性肝病的动脉重塑

• 批准号: 8500246
• 负责人: YASUKO IWAKIRI
• 金额: $ 34.05万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500246
• 关键词: Arteries; Attention; Blood Circulation; Blood Vessels; Blood flow; Cells; Chronic; Cirrhosis; Endothelium; Extracellular Matrix; Functional disorder; Gelatinase A; Goals; Golgi Apparatus; Health; Hemorrhage; In Vitro; Knockout Mice; Lead; Life; Liver; Liver Cirrhosis; Liver diseases; Matrix Metalloproteinases; Mediating; Membrane; Molecular; Morphology; Mus; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Patients; Phenotype; Play; Portal Hypertension; Post-Translational Protein Processing; Process; Proteins; Rattus; Regulation; Research; Role; Splanchnic Circulation; Structure; Superior mesenteric artery structure; Testing; Tumor Vascular Invasion; Vascular Diseases; Vascular remodeling; arterial remodeling; chronic liver disease; hemodynamics; human NOS3 protein; in vivo; mortality; pressure; response; therapy development

DESCRIPTION (provided by applicant): In liver cirrhosis, chronic portal hypertension causes hemodynamic abnormalities and leads to thinning of the arterial wall in the splanchnic and systemic circulation. Thinning of the arterial wall leads to permanent dysfunction of arterial tone and worsens hemodynamic abnormalities, resulting in the most lethal complications of liver disease such as variceal hemorrhage. Overproduction of nitric oxide (NO) in arteries, which is generated by elevated activity of endothelia NO synthase (eNOS), plays a central role in arterial wall thinning. However, the mechanism by which NO mediates this process is unknown. The objective of our proposed research is to elucidate the molecular mechanism of arterial wall thinning in chronic liver disease. EMMPRIN, extracellular matrix metalloproteinase inducer, plays an important role in vascular remodeling and tumor invasion, by inducing activation of matrix metalloproteinases (MMPs), such as MMP-2. We found that both EMMPRIN expression and MMP-2 activation were significantly elevated in the superior mesenteric artery (SMA; an artery in the splanchnic circulation) in cirrhotic rats. Furthermore, we identified EMMPRIN as a target for S-nitrosylation, an important post-translational modification mediated by NO. Thus, we hypothesize that enhanced eNOS-derived NO may induce EMMPRIN activation through S-nitrosylation, which in turn causes MMP-2 activation, leading to thinning of the arterial wall in the SMA in cirrhosis. This hypothesis will be tested through the following three Specific Aims: 1. Identify the role of eNOS-derived NO in the regulation of EMMPRIN. 2. Determine the roles of eNOS and EMMPRIN in the activation of MMP-2. 3. Determine the roles of eNOS, EMMPRIN and MMP-2 in thinning of the arterial wall in the splanchnic circulation in cirrhotic mice. Findings from these aims will define the roles of eNOS, EMMPRIN and MMP-2 in arterial wall thinning in vivo and demonstrate the mechanism of this response. These findings could be used to develop therapies for patients with chronic liver disease. Furthermore, it is likely that our findings will be relevant to other vascular diseases.

描述（由申请人提供）：在肝肝硬化中，慢性门户高血压会导致血液动力学异常，并导致腹膜和全身循环中的动脉壁变薄。动脉壁的变薄会导致动脉张力的永久功能障碍，并使血液动力学异常恶化，从而导致肝病最致命的并发症，例如静脉曲张出血。动脉中一氧化氮（NO）的过量生产，这是由内皮NO合酶（ENOS）活性升高而产生的，在动脉壁稀疏中起着核心作用。但是，没有介导此过程的机制尚不清楚。我们提出的研究的目的是阐明慢性肝病中动脉壁稀疏的分子机制。细胞外基质金属蛋白酶诱导酶Emmprin通过诱导基质金属蛋白酶（MMP）（例如MMP-2）的激活，在血管重塑和肿瘤侵袭中起重要作用。我们发现，在肝硬化大鼠的上肠系膜上动脉（SMA；斜虫循环中的动脉）中，Emmprin的表达和MMP-2激活显着升高。此外，我们将Emmprin确定为S-亚硝基化的靶标，这是由NO介导的重要的翻译后修饰。因此，我们假设增强的eNOS衍生的NO可能会通过S-硝基化诱导Emmprin激活，这反过来导致MMP-2激活，从而导致SMA中的动脉壁在肝硬化中变薄。该假设将通过以下三个特定目的进行检验：1。确定eNOS衍生的NO在Emmprin调节中的作用。 2。确定eNOS和Emmprin在MMP-2激活中的作用。 3。确定肝硬化小鼠中闪烁的动脉循环中eNOS，Emmprin和MMP-2在稀疏中的作用。这些目标的发现将定义eNOS，Emmprin和MMP-2在体内稀疏中的作用，并证明了这种反应的机制。这些发现可用于为患有慢性肝病的患者开发疗法。此外，我们的发现可能与其他血管疾病有关。