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.
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.
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