Arterial Remodeling in Chronic Liver Diseases

Summary

Principal Investigator: Yasuko Iwakiri
Abstract: 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.
Funding Period: 2009-07-01 - 2014-06-30
more information: NIH RePORT

Top Publications

  1. pmc The type III inositol 1,4,5-trisphosphate receptor is associated with aggressiveness of colorectal carcinoma
    Kazunori Shibao
    Department of Surgery I, University of Occupational and Environmental Health School of Medicine, Yahatanishi ku, Kitakyushu, Japan
    Cell Calcium 48:315-23. 2010
  2. pmc Pathophysiology of portal hypertension
    Yasuko Iwakiri
    Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, 1080 LMP, 333 Cedar Street, New Haven, CT 06520, USA Electronic address
    Clin Liver Dis 18:281-91. 2014
  3. pmc Reticulon 4 is necessary for endoplasmic reticulum tubulation, STIM1-Orai1 coupling, and store-operated calcium entry
    Levente Jozsef
    From the Vascular Biology and Therapeutics Program, Department of Pharmacology
    J Biol Chem 289:9380-95. 2014
  4. pmc eNOS-derived nitric oxide regulates endothelial barrier function through VE-cadherin and Rho GTPases
    Annarita Di Lorenzo
    Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA
    J Cell Sci 126:5541-52. 2013
  5. pmc Determination of mesenchymal stem cell fate by pigment epithelium-derived factor (PEDF) results in increased adiposity and reduced bone mineral content
    Arijeet K Gattu
    1Section of Digestive Diseases, Department of Medicine, Yale University School of Medicine, 1080 LMP, New Haven, CT, USA
    FASEB J 27:4384-94. 2013
  6. pmc The lymphatic vascular system in liver diseases: its role in ascites formation
    Chuhan Chung
    Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
    Clin Mol Hepatol 19:99-104. 2013
  7. pmc Absence of Nogo-B (reticulon 4B) facilitates hepatic stellate cell apoptosis and diminishes hepatic fibrosis in mice
    Keitaro Tashiro
    Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Am J Pathol 182:786-95. 2013
  8. pmc Reticulon 4B (Nogo-B) facilitates hepatocyte proliferation and liver regeneration in mice
    Lili Gao
    Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
    Hepatology 57:1992-2003. 2013
  9. pmc Proteomic identification of S-nitrosylated Golgi proteins: new insights into endothelial cell regulation by eNOS-derived NO
    Panjamaporn Sangwung
    Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
    PLoS ONE 7:e31564. 2012
  10. pmc Intestinal and plasma VEGF levels in cirrhosis: the role of portal pressure
    Hui Chun Huang
    Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
    J Cell Mol Med 16:1125-33. 2012

Detail Information

Publications15

  1. pmc The type III inositol 1,4,5-trisphosphate receptor is associated with aggressiveness of colorectal carcinoma
    Kazunori Shibao
    Department of Surgery I, University of Occupational and Environmental Health School of Medicine, Yahatanishi ku, Kitakyushu, Japan
    Cell Calcium 48:315-23. 2010
    ..These findings suggest a previously unrecognized role for Ca(2+) signaling via this InsP3R isoform in colon cancer...
  2. pmc Pathophysiology of portal hypertension
    Yasuko Iwakiri
    Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, 1080 LMP, 333 Cedar Street, New Haven, CT 06520, USA Electronic address
    Clin Liver Dis 18:281-91. 2014
    ..In addition, the future directions of basic/clinical research in portal hypertension are discussed. ..
  3. pmc Reticulon 4 is necessary for endoplasmic reticulum tubulation, STIM1-Orai1 coupling, and store-operated calcium entry
    Levente Jozsef
    From the Vascular Biology and Therapeutics Program, Department of Pharmacology
    J Biol Chem 289:9380-95. 2014
    ..Thus, for the first time, our results show a direct correlation between ER morphology and SOCE and highlight the importance of RTN4 in cellular Ca(2+) homeostasis. ..
  4. pmc eNOS-derived nitric oxide regulates endothelial barrier function through VE-cadherin and Rho GTPases
    Annarita Di Lorenzo
    Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA
    J Cell Sci 126:5541-52. 2013
    ..Thus, NO is crucial for Rho GTPase-dependent regulation of cytoskeletal architecture leading to reversible changes in vascular permeability...
  5. pmc Determination of mesenchymal stem cell fate by pigment epithelium-derived factor (PEDF) results in increased adiposity and reduced bone mineral content
    Arijeet K Gattu
    1Section of Digestive Diseases, Department of Medicine, Yale University School of Medicine, 1080 LMP, New Haven, CT, USA
    FASEB J 27:4384-94. 2013
    ..Bones from KO mice demonstrated a reduction in mineral content recapitulating the OI type VI phenotype. These results demonstrate that the human diseases associated with PEDF reflect its ability to modulate MSC differentiation...
  6. pmc The lymphatic vascular system in liver diseases: its role in ascites formation
    Chuhan Chung
    Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
    Clin Mol Hepatol 19:99-104. 2013
    ..This article summarizes: 1) the lymphatic vascular system; 2) its role in liver tumors, liver fibrosis/cirrhosis and portal hypertension; and 3) its role in ascites formation. ..
  7. pmc Absence of Nogo-B (reticulon 4B) facilitates hepatic stellate cell apoptosis and diminishes hepatic fibrosis in mice
    Keitaro Tashiro
    Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Am J Pathol 182:786-95. 2013
    ..The absence of Nogo-B enhances apoptosis of HSCs in experimental cirrhosis. Selective blockade of Nogo-B in HSCs may represent a potential therapeutic strategy to mitigate liver fibrosis...
  8. pmc Reticulon 4B (Nogo-B) facilitates hepatocyte proliferation and liver regeneration in mice
    Lili Gao
    Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
    Hepatology 57:1992-2003. 2013
    ..Lack of Nogo-B delayed hepatocyte proliferation but did not affect the liver-to-body ratio in the regenerative process...
  9. pmc Proteomic identification of S-nitrosylated Golgi proteins: new insights into endothelial cell regulation by eNOS-derived NO
    Panjamaporn Sangwung
    Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
    PLoS ONE 7:e31564. 2012
    ..The aim of this study was to identify S-nitrosylated Golgi proteins and attribute their S-nitrosylation to eNOS-derived nitric oxide in endothelial cells...
  10. pmc Intestinal and plasma VEGF levels in cirrhosis: the role of portal pressure
    Hui Chun Huang
    Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
    J Cell Mol Med 16:1125-33. 2012
    ..01), compared to the controls (8.5 pg/ml). However, no correlation was observed between PP and plasma VEGF levels. It is concluded that portal pressure modulates intestinal VEGF levels during the development of cirrhosis...
  11. pmc Endothelial dysfunction in the regulation of cirrhosis and portal hypertension
    Yasuko Iwakiri
    Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
    Liver Int 32:199-213. 2012
    ..The article ends by discussing the future directions of the study for endothelial dysfunction...
  12. pmc S-nitrosylation of proteins: a new insight into endothelial cell function regulated by eNOS-derived NO
    Yasuko Iwakiri
    Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
    Nitric Oxide 25:95-101. 2011
    ..g., exocytosis and endocytosis), redox state, and cell cycle. Thus, eNOS-derived NO regulates a wide range of endothelial cell functions, such as inflammation, apoptosis, permeability, migration, and cell growth...
  13. pmc Reticulon 4B (Nogo-B) is a novel regulator of hepatic fibrosis
    Dahai Zhang
    Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
    Hepatology 53:1306-15. 2011
    ..Four weeks after BDL, portal pressure was significantly increased in WT mice by 47%, compared with sham-operated controls (P = 0.03), whereas such an increase in portal pressure was not observed in NGB KO mice (P = NS)...

Research Grants30

  1. Pathogenesis and Diagnosis of Multiple System Atrophy (P01)
    Phillip A Low; Fiscal Year: 2013
    ..The study will be conjointly carried out by Projects 1 and 4 and supported by Core A. These projects will continue to be supported by 3 cores. ..
  2. GENE THERAPY FOR HEMOPHILIA
    Katherine A High; Fiscal Year: 2013
    ..The projects are highly interactive, and all three take full advantage of the proposed cores. ..
  3. MULTIDISCIPLINARY STRUCTURES AT VASCULAR CELL SURFACES
    Timothy A Springer; Fiscal Year: 2013
    ..Administrative (Springer) and Protein Expression (Lu) Cores enhance efficiency of the PPG. (End of Abstract) ..
  4. Diverse Roles of Reactive Oxygen Species and Inflammation in Vascular Disease
    Kathy K Griendling; Fiscal Year: 2013
    ..Ultimately, this research may establish new unifying concepts linking conditions that alter vascular oxidant stress and inflammation to the molecular processes underlying vasculopathies. (End of Abstract) ..
  5. Quantitative Hemodynamics of the Liver with 4D Flow MRI
    Oliver Wieben; Fiscal Year: 2013
    ....
  6. Endothelial Myocyte Matrix in Cardiac Remodeling
    Suresh C Tyagi; Fiscal Year: 2013
    ..PHS 398/2590 (Rev. 11/07) Page Continuation Format Page ..
  7. Maternal Uterine Vascular Origins of Fetal Alcohol Spectrum Disorders
    Jayanth Ramadoss; Fiscal Year: 2013
    ..abstract_text> ..
  8. PPG - Gene Therapy for Cystic Fibrosis Lung Disease
    Paul B McCray; Fiscal Year: 2013
    ..The discoveries from this PPG will accelerate the development of gene-based medicine for patients who suffer from this devastating disease...
  9. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
    ..Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma. ..
  10. Targeting epithelial cells to treat pulmonary fibrosis
    Dean Sheppard; Fiscal Year: 2013
    ..abstract_text> ..
  11. Calcium signaling in the cerebrovascular unit in health and disease
    Mark T Nelson; Fiscal Year: 2013
    ..The long-term objective is to understand blood flow in the brain in health and disease, and by doing so, to reveal exciting novel targets that can be exploited in the treatment of cerebrovascular disease. ..
  12. Interactive Signaling Modules in Vascular Inflammation
    Linda H Shapiro; Fiscal Year: 2013
    ..abstract_text> ..
  13. Biomechanical Mechanisms of Artery Tortuosity
    Hai Chao Han; Fiscal Year: 2013
    ..Understanding the biomechanical mechanisms how tortuosity initiates and develop will reveal its role in vascular disease and lead to new understanding of vascular disease and set a basis for development of new treatment. ..
  14. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  15. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  16. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  17. Peptide Therapy for Pulmonary Arterial Hypertension
    Jawaharlal M Patel; Fiscal Year: 2013
    ..Confirmation of the mechanism-based physiological approach for NO releasing PDE5 inhibitor function of this novel peptide in preclinical animal model is innovative for progression towards Phase I clinical trial for treatment of PH. ..
  18. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  19. INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION
    R John Solaro; Fiscal Year: 2013
    ..Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies. (End of Abstract) ..
  20. Carbon monoxide and vascular cell function
    William Durante; Fiscal Year: 2013
    ..This project will explore the possible therapeutic application of low doses of carbon monoxide in preventing the blockage of arteries and in treating high blood pressure. ..
  21. Induction of uterine vascular remodeling by myometrial stretch
    George J Osol; Fiscal Year: 2013
    ....
  22. Essential Hypertension and Human Skin Blood Flow
    Lacy M Alexander; Fiscal Year: 2013
    ..Further, these results will provide insight into the regulation of skin blood flow and potential therapeutic intervention strategies for hypertensive vascular pathology. ..
  23. Multiple Molecular Mechanisms for Adiponectin Therapy in Hepatic Fibrogenesis
    Frank A Anania; Fiscal Year: 2013
    ....
  24. AMPK Endothelial Cell Dysfunction and the Metabolic Syndrome (PROGRAM PROJECT)
    Neil B Ruderman; Fiscal Year: 2013
    ..The proposed studies should both yield novel insights into the biological bases for the premature atherosclerosis and impaired angiogenesis associated with this entity and suggest new therapeutic targets for their prevention...
  25. An Integrated Biometric Platform for Evaluation of Nanomedicine Delivery
    Yaling Liu; Fiscal Year: 2013
    ..This methodology will enable accurate and efficient estimation of nanoparticle biodistribution in patient-specific vascular geometries. ..
  26. Endothelial Barrier Protection and Repair in Acute Lung Injury
    Stephen M Black; Fiscal Year: 2013
    ..abstract_text> ..