Arterial Remodeling in Chronic Liver Diseases

描述(申请人提供)：在肝硬变中，慢性门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。动脉壁变薄会导致永久性动脉张力障碍，加重血流动力学异常，导致肝病最致命的并发症，如静脉曲张出血。内皮型一氧化氮合酶(ENOS)活性升高导致动脉内一氧化氮(NO)过量生成，在动脉壁变薄中起重要作用。然而，NO调节这一过程的机制尚不清楚。我们提出的研究目的是阐明慢性肝病中动脉壁变薄的分子机制。EMMPRIN是一种细胞外基质金属蛋白酶诱导剂，通过诱导基质金属蛋白酶(MMPs)的激活，在血管重塑和肿瘤侵袭中发挥重要作用。我们发现，在肝硬变大鼠肠系膜上动脉(SMA；内脏循环中的一条动脉)上，EMMPRIN的表达和基质金属蛋白酶-2的活性均显著升高。此外，我们确定EMMPRIN是由NO介导的一种重要的翻译后修饰-S亚硝化的靶点。因此，我们推测，增强eNOS来源的NO可能通过S-亚硝化诱导EMMPRIN激活，进而导致基质金属蛋白酶-2激活，导致肝硬变时SMA动脉壁变薄。这一假说将通过以下三个具体目标来验证：1.确定eNOS来源的NO在EMMPRIN调控中的作用。2.确定eNOS和EMMPRIN在基质金属蛋白酶-2活化中的作用。3.探讨内皮型一氧化氮合酶(ENOS)、内皮型一氧化氮合酶(EMMPRIN)和基质金属蛋白酶-2在肝硬变小鼠内脏循环动脉壁变薄中的作用。这些目标的发现将确定eNOS、EMMPRIN和基质金属蛋白酶-2在体内动脉壁变薄中的作用，并阐明这种反应的机制。这些发现可能被用来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。与公众健康相关：危及生命的肝病并发症，如静脉曲张出血，其死亡率超过50%，实际上是由于血管结构异常，导致进入肝脏的血液流动受到限制，导致血液循环中的压力和流量发生慢性变化。在肝脏疾病的研究中，与肝脏病理生物学相比，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。

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.