Arterial Remodeling in Chronic Liver Diseases

描述（由申请人提供）：在肝硬化患者中，慢性门静脉高压导致血流动力学异常，并导致内脏和体循环中动脉壁变薄。动脉壁变薄导致动脉张力的永久性功能障碍和动脉血流动力学异常，导致最致命的肝病并发症，如静脉曲张出血。血管内皮细胞一氧化氮合酶（eNOS）活性升高导致血管内一氧化氮（NO）过量生成，在动脉壁变薄中起重要作用。然而，NO介导这一过程的机制尚不清楚。本研究的目的是阐明慢性肝病动脉壁变薄的分子机制。EMMPRIN是细胞外基质金属蛋白酶诱导因子，通过诱导基质金属蛋白酶（MMP-2）的活化，在血管重塑和肿瘤侵袭中发挥重要作用。我们发现，EMMPRIN的表达和MMP-2的活化显着升高，在上级肠系膜动脉（SMA;动脉在内脏循环）在糖尿病大鼠。此外，我们确定EMMPRIN作为S-亚硝基化的目标，一个重要的翻译后修饰介导的NO。因此，我们假设，增强eNOS衍生的NO可能会诱导EMMPRIN激活通过S-亚硝基化，这反过来又会导致MMP-2激活，导致变薄的动脉壁在SMA在肝硬化。这一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活化中的作用。3.探讨内皮型一氧化氮合酶（eNOS）、基质金属蛋白酶-2（MMP-2）和细胞外基质金属蛋白酶（EMMPRIN）在动脉壁变薄中的作用。这些目标的发现将定义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：肝脏疾病的危及生命的并发症，例如其死亡率超过50%的静脉曲张出血，实际上是由于异常的血管结构，由进入肝脏的血流受限引起的血液循环中的压力和流量的慢性变化引起的。在肝脏疾病的研究中，这些血管异常与肝脏病理学相比受到的关注较少，尽管它们与这些致命并发症的关系最密切。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。

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.