Arterial Remodeling in Chronic Liver Diseases

慢性肝病的动脉重塑

• 批准号: 7848984
• 负责人: YASUKO IWAKIRI
• 金额: $ 39.32万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848984
• 关键词: Arteries; Attention; Blood Circulation; Blood Vessels; Blood flow; Cells; Chronic; Cirrhosis; Endothelium; Extracellular Matrix; Functional disorder; Gelatinase A; Goals; Golgi Apparatus; 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 Cell Invasion; Vascular Diseases; Vascular remodeling; arterial remodeling; hemodynamics; human NOS3 protein; in vivo; mortality; pressure; public health relevance; 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. PUBLIC HEALTH RELEVANCE: Life-threatening complications of liver disease, such as variceal hemorrhage with its mortality rate exceeding 50%, are in fact due to abnormal blood vessel structures, resulting from chronic changes in the pressure and flow in the blood circulation initiated by the restriction of blood flow coming into the liver. In the study of liver disease, these abnormalities in blood vessels have received less attention compared to the liver pathobiology despite their closest association with such lethal complications. Thus, the goal of our proposed research is to understand the detailed mechanisms of how these vessel structures are changed in chronic liver disease.

描述（由申请人提供）：在肝硬化中，慢性门静脉高压会导致血流动力学异常，并导致内脏和体循环中的动脉壁变薄。动脉壁变薄导致动脉张力永久性功能障碍，并使血流动力学异常恶化，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) 的过量产生是由内皮一氧化氮合酶 (eNOS) 活性升高产生的，在动脉壁变薄中发挥着核心作用。然而，NO 介导这一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变薄的分子机制。 EMMPRIN 是细胞外基质金属蛋白酶诱导剂，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发挥重要作用。我们发现肝硬化大鼠肠系膜上动脉（SMA；内脏循环中的动脉）中 EMMPRIN 表达和 MMP-2 激活均显着升高。此外，我们确定 EMMPRIN 是 S-亚硝基化的靶标，S-亚硝基化是 NO 介导的重要翻译后修饰。因此，我们假设增强的 eNOS 衍生的 NO 可能通过 S-亚硝基化诱导 EMMPRIN 激活，进而引起 MMP-2 激活，导致肝硬化时 SMA 中的动脉壁变薄。该假设将通过以下三个具体目标进行检验： 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eNOS、EMMPRIN和MMP-2在肝硬化小鼠内脏循环动脉壁变薄中的作用。这些目标的发现将明确 eNOS、EMMPRIN 和 MMP-2 在体内动脉壁变薄中的作用，并证明这种反应的机制。这些发现可用于开发慢性肝病患者的治疗方法。此外，我们的发现很可能与其他血管疾病相关。公共卫生相关性：危及生命的肝病并发症，例如死亡率超过 50% 的静脉曲张出血，实际上是由于血管结构异常造成的，而异常血管结构是由肝脏引起的血液循环压力和流量的慢性变化造成的。限制进入肝脏的血流。在肝脏疾病的研究中，与肝脏病理学相比，这些血管异常受到的关注较少，尽管它们与此类致命并发症密切相关。因此，我们提出的研究的目标是了解这些血管结构在慢性肝病中如何改变的详细机制。