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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK082600-05S1
Application #
8724090
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$88,528
Indirect Cost
$35,358
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Park, Jin-Kyu; Utsumi, Teruo; Seo, Young-Eun et al. (2016) Cellular distribution of injected PLGA-nanoparticles in the liver. Nanomedicine 12:1365-74
Iwakiri, Yasuko (2016) The lymphatic system: A new frontier in hepatology. Hepatology 64:706-7
Mookerjee, Rajeshwar P; Mehta, Gautam; Balasubramaniyan, Vairappan et al. (2015) Hepatic dimethylarginine-dimethylaminohydrolase1 is reduced in cirrhosis and is a target for therapy in portal hypertension. J Hepatol 62:325-31
Wang, Shuxia; Song, Kangxing; Srivastava, Roshni et al. (2015) Nonalcoholic fatty liver disease induced by noncanonical Wnt and its rescue by Wnt3a. FASEB J 29:3436-45
Hidaka, Hisashi; Iwakiri, Yasuko (2015) Hepatic congestion leads to fibrosis: findings in a newly developed murine model. Hepatology 61:428-30
Protiva, Petr; Gong, Jingjing; Sreekumar, Bharath et al. (2015) Pigment Epithelium-Derived Factor (PEDF) Inhibits Wnt/β-catenin Signaling in the Liver. Cell Mol Gastroenterol Hepatol 1:535-549
Kim, Moon Young; Iwakiri, Yasuko (2015) Can hypersplenism secondary to portal hypertension be treated by non-selective beta blockers? Hepatol Int 9:337-8
Iwakiri, Yasuko; Kim, Moon Young (2015) Nitric oxide in liver diseases. Trends Pharmacol Sci 36:524-36
Iwakiri, Yasuko (2015) Nitric oxide in liver fibrosis: The role of inducible nitric oxide synthase. Clin Mol Hepatol 21:319-25
Kurobe, Hirotsugu; Maxfield, Mark W; Tara, Shuhei et al. (2015) Development of small diameter nanofiber tissue engineered arterial grafts. PLoS One 10:e0120328

Showing the most recent 10 out of 29 publications