Nitric Oxide and the Cellular Pathogenesis of Portal Hypertension

Summary

Principal Investigator: Don C Rockey
Abstract: Increased intrahepatic resistance to blood flow is an important component of many forms of portal hypertension. We and others have recently demonstrated that perisinusoidal stellate cells (Ito cells or lipocytes) exhibit a contractile phenotype and play an important role in regulation of sinusoidal blood flow. The dynamic nature of blood flow regulation within the hepatic sinusoid (or capillary in the systemic circulation) emphasizes the importance of interplay between vasoconstrictive and vasodilatory compounds. ET-1, a potent vasoactive peptide, is overproduced after liver injury and appears to contribute to increased intrahepatic resistance via contraction of stellate cells. In contrast, nitric oxide (NO), a key molecule in normal vascular homeostasis, has been identified as an important relaxing factor for stellate cells, and balances the effect of ET- 1. Available data therefore suggest that the balance of such vasoregulatory elements helps determine the degree of resistance within the hepatic microcirculatory unit. We have shown that after liver injury, NO synthesis is reduced. The abnormality has been localized to defective NO synthase (eNOS) dependent NO release by sinusoidal endothelial cells. Further, preliminary data presented in the current application have identified specific post-translational defects in eNOS after liver injury, including reduced phosphorylation of eNOS by the protein kinase, Akt. New data indicate that GRK2 interacts with and affects Akt activity. These data have led us to hypothesize that post-translational defects in eNOS after liver injury are critical in establishment of the sinusoidal endothelialopathy present after liver injury. The overall goal of the PI is to elucidate the cell and molecular basis of increased intrahepatic resistance with a focus on sinusoidal endothelial cells and eNOS. The specific aims of the current proposal are (1) to examine eNOS phosphorylation in the normal and injured liver, (2) to understand caveolin-1 expression and regulation in SECs, and (3) to investigate the role of GRK2 in regulation of Akt and eNOS function. The proposed experiments have important therapeutic implications not only for patients with liver disease and portal hypertension, but also across much of vascular biology. PUBLIC HEALTH RELEVANCE: Liver damage leads to elevated resistance to blood flow through the liver. This leads to intestinal bleeding and severe clinical consequences. This proposal aims to understand the cause of elevated resistance to blood flow and would shed light on potential treatments for this problem.
Funding Period: -------------------- - --------------------
more information: NIH RePORT

Top Publications

  1. ncbi Noninvasive measures of liver fibrosis
    Don C Rockey
    Department of Medicine, and the Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Hepatology 43:S113-20. 2006
  2. pmc Cicletanine stimulates eNOS phosphorylation and NO production via Akt and MAP kinase/Erk signaling in sinusoidal endothelial cells
    Songling Liu
    Department of Internal Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
    Am J Physiol Gastrointest Liver Physiol 305:G163-71. 2013
  3. pmc Translating an understanding of the pathogenesis of hepatic fibrosis to novel therapies
    Don C Rockey
    Department of Internal Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    Clin Gastroenterol Hepatol 11:224-31.e1-5. 2013
  4. ncbi Effect of the nitric oxide donor V-PYRRO/NO on portal pressure and sinusoidal dynamics in normal and cirrhotic mice
    Claire Edwards
    Department of Medicine, Duke University Medical Center, Durham, NC, USA
    Am J Physiol Gastrointest Liver Physiol 294:G1311-7. 2008
  5. ncbi New therapies in hepatitis C virus and chronic liver disease: antifibrotics
    Don C Rockey
    Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 8887, USA
    Clin Liver Dis 10:881-900. 2006
  6. ncbi Hepatic fibrosis, stellate cells, and portal hypertension
    Don C Rockey
    Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 8887, USA
    Clin Liver Dis 10:459-79, vii-viii. 2006
  7. ncbi Interferon gamma-1b for the treatment of fibrosis in chronic hepatitis C infection
    A J Muir
    Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
    J Viral Hepat 13:322-8. 2006
  8. ncbi Pharmacologic therapy for gastrointestinal bleeding due to portal hypertension and esophageal varices
    Don C Rockey
    Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 8887, USA
    Curr Gastroenterol Rep 8:7-13. 2006
  9. pmc Smooth muscle α actin (Acta2) and myofibroblast function during hepatic wound healing
    Don C Rockey
    Department of Internal Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America
    PLoS ONE 8:e77166. 2013
  10. pmc G-protein-coupled receptor kinase interactor-1 (GIT1) is a new endothelial nitric-oxide synthase (eNOS) interactor with functional effects on vascular homeostasis
    Songling Liu
    University of Texas Southwestern Medical Center, Division of Digestive and Liver Diseases, Dallas, Texas 75390, USA
    J Biol Chem 287:12309-20. 2012

Detail Information

Publications10

  1. ncbi Noninvasive measures of liver fibrosis
    Don C Rockey
    Department of Medicine, and the Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Hepatology 43:S113-20. 2006
    ..The development of safe, inexpensive, and reliable noninvasive fibrosis measurement tools remains a research priority in clinical hepatology...
  2. pmc Cicletanine stimulates eNOS phosphorylation and NO production via Akt and MAP kinase/Erk signaling in sinusoidal endothelial cells
    Songling Liu
    Department of Internal Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
    Am J Physiol Gastrointest Liver Physiol 305:G163-71. 2013
    ..It raises the possibility that cicletanine could improve intrahepatic vascular function in portal hypertensive patients...
  3. pmc Translating an understanding of the pathogenesis of hepatic fibrosis to novel therapies
    Don C Rockey
    Department of Internal Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    Clin Gastroenterol Hepatol 11:224-31.e1-5. 2013
    ..This review highlights the mechanisms underlying fibrogenesis that may be translated into future antifibrotic therapies and to review the current state of clinical development...
  4. ncbi Effect of the nitric oxide donor V-PYRRO/NO on portal pressure and sinusoidal dynamics in normal and cirrhotic mice
    Claire Edwards
    Department of Medicine, Duke University Medical Center, Durham, NC, USA
    Am J Physiol Gastrointest Liver Physiol 294:G1311-7. 2008
    ..As the potential of this or other similar compounds for treatment of portal hypertension is evaluated, effects on the systemic vasculature will also need to be considered...
  5. ncbi New therapies in hepatitis C virus and chronic liver disease: antifibrotics
    Don C Rockey
    Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 8887, USA
    Clin Liver Dis 10:881-900. 2006
    ..The aggregate data has not only helped lead to an understanding of the pathophysiologic basis of hepatic fibrogenesis, but it has also provided an important context with which to base novel antifibrotic therapy...
  6. ncbi Hepatic fibrosis, stellate cells, and portal hypertension
    Don C Rockey
    Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 8887, USA
    Clin Liver Dis 10:459-79, vii-viii. 2006
    ..Given the central role of stellate cell activation in hepatic fibrogenesis (and portal hypertension), effective therapy for hepatic fibrogenesis is most likely will be directed at this event...
  7. ncbi Interferon gamma-1b for the treatment of fibrosis in chronic hepatitis C infection
    A J Muir
    Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
    J Viral Hepat 13:322-8. 2006
    ..These data provide a basis for further study of interferon gamma-1b in patients with chronic fibrosing liver disease...
  8. ncbi Pharmacologic therapy for gastrointestinal bleeding due to portal hypertension and esophageal varices
    Don C Rockey
    Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 8887, USA
    Curr Gastroenterol Rep 8:7-13. 2006
    ..For primary and secondary prevention of esophageal variceal hemorrhage, beta-blockers remain the mainstay therapy...
  9. pmc Smooth muscle α actin (Acta2) and myofibroblast function during hepatic wound healing
    Don C Rockey
    Department of Internal Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America
    PLoS ONE 8:e77166. 2013
    ....
  10. pmc G-protein-coupled receptor kinase interactor-1 (GIT1) is a new endothelial nitric-oxide synthase (eNOS) interactor with functional effects on vascular homeostasis
    Songling Liu
    University of Texas Southwestern Medical Center, Division of Digestive and Liver Diseases, Dallas, Texas 75390, USA
    J Biol Chem 287:12309-20. 2012
    ..Re-expression of GIT1 after liver injury rescued the endothelial phenotype. These data emphasize the role of GPCR signaling partners in eNOS function and have fundamental implications for vascular disorders involving dysregulated eNOS...