Fc gamma RIIB and Inflammation-Related Vascular Disease

Summary

Principal Investigator: Philip W Shaul
Abstract: DESCRIPTION (provided by applicant): Fc receptors (FcR) classically modulate responses to IgG in B cells and other effector cells in the immune system. We discovered that the inhibitory FcR, Fc?RIIB, is abundant in endothelium, and that it mediates endothelial NO synthase (eNOS) antagonism by IgG, C-reactive protein (CRP) and serum amyloid P component (SAP), which is the CRP-equivalent in mice. The eNOS antagonism occurs via inhibition of Akt and eNOS activating phosphorylation. Since in mice endothelial Akt and eNOS activating phosphorylation are similarly attenuated in association with obesity-induced hypertension (HTN), global Fc?RIIB-/- mice were placed on high-fat diet (HFD) and it was discovered that despite weight gain equal to that of Fc?RIIB+/+, the null mice are protected from obesity-induced HTN. The OVERALL GOAL of the proposal is to determine how Fc?RIIB contributes to the pathogenesis of obesity-induced HTN. Aim 1 is to determine how endothelial cell Fc?RIIB participates in the disorder. Using radiotelemetry, BP will be compared in wild-type mice vs. mice with endothelial cell-specific Fc?RIIB deletion on normal chow vs. HFD. HFD-induced changes in vascular Akt and eNOS phosphorylation state will be evaluated in these groups, and potential protection from the HTN will be assessed in mice expressing constitutively-active Akt selectively in endothelium. An anti-Fc?RIIB blocking antibody will be used to determine if an intervention targeting the receptor prevents the HTN. Aim 2 is to identity the Fc?RIIB ligand(s) mediating obesity-induced HTN. We've discovered that SAP increases in mice on HFD, and that IgG isolated from HFD-fed mice potently antagonizes eNOS in cultured endothelium, whereas IgG from normal chow-fed mice does not. HFD-induced HTN will therefore be studied in wild-type vs. SAP-/- and immunoglobulin u heavy-chain null mice deficient in B cells and IgG. If this work implicates IgG, a B cell depleting antibody and an FcRn-directed agent that enhances IgG degradation will be used to determine if interventions that decrease Fc?RIIB ligand abundance prevent obesity-induced HTN. Aim 3 is to determine how Fc?RIIB influences the development of HTN in humans with elevated pentraxin levels or obesity. The association between common single nucleotide polymorphisms (SNP) in Fc?RIIB and incident HTN will be evaluated in the Women's Genome Health Study, which is a prospective cohort study of over 25,000 women. Impetus includes the discovery of an Fc?RIIB variant incapable of eNOS antagonism and a preliminary query of subjects with CRP>2.0mg/L in the Dallas Heart Study;in African Americans in whom genotype frequency provided sufficient statistical power, the loss-of-function variant was associated with lower systolic BP. By accomplishing these aims, the novel concept will be tested that Fc?RIIB in endothelium and FcR ligands participate in the pathogenesis of HTN. Unique preventative or treatment measures to combat the HTN that complicates obesity and other chronic inflammatory conditions will potentially follow.
Funding Period: 2013-08-16 - 2017-06-30
more information: NIH RePORT

Detail Information

Research Grants30

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  2. Discovery of Novel Interventions of the Antiphospholipid Syndrome
    Chieko Mineo; Fiscal Year: 2013
    ..Together these aims will determine how aPL cause leukocyte adhesion and thrombosis and test potential therapeutic strategies to prevent aPL-mediated vascular dysfunction. ..
  3. Toll-Like Receptors in Systemic Autoimmune Disease
    Ann Marshak-Rothstein; Fiscal Year: 2013
    ....
  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. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
  6. RAGE and Mechanisms of Vascular Dysfunction
    Shi Fang Yan; Fiscal Year: 2013
    ..Using novel and state-of-the-art techniques, floxed mice and molecular approaches to gene regulation, we are well-positioned to lead the study of RAGE in the next cycle of this Program. ..
  7. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  8. 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...
  9. Zimmerman Program for the Molecular and Clinical Biology of VWD
    Robert R Montgomery; Fiscal Year: 2013
    ..Taken together this PPG will set the stage for the appropriate diagnosis and phenotypic understanding of VWD - both in the US and throughout the world. ..
  10. Ether Lipids, Elcosanoids, and Lung Cell Pathophysiology
    CHRISTINA CARROLL LESLIE; Fiscal Year: 2013
    ..By using multidisciplinary approaches, we will determine the structural identity of lipid mediators, the molecular mechanisms involved in their production and how they function to regulate lung responses. ..
  11. NEW MODALITIES FOR TREATMENT OF PAIN AND DRUG ABUSE
    Victor J Hruby; Fiscal Year: 2013
    ....
  12. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  13. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  14. Hopkins Center for Eliminate Cardiovascular Health Disparities
    Lisa A Cooper; Fiscal Year: 2013
    ..abstract_text> ..
  15. New Approaches To Cardiothoracic Tolerance Induction
    Joren C Madsen; Fiscal Year: 2013
    ..We anticipate ongoing progress will continue to contribute to a reduction in the morbidity and mortality associated with solid organ transplantation. ..
  16. Autoimmunity Center of Excellence (ACE) at Stanford
    CHARLES GARRISON FATHMAN; Fiscal Year: 2013
    ..The Stanford ACE proposes clinical research projects that encompass three different autoimmune diseases (SSc, psoriatic arthritis and SJIA), and proposes to study the MoA of therapeutics for preventing or treating different Al diseases. ..
  17. Mechanisms of Microvascular Control and Coordination in Health and Disease
    Gerald A Meininger; Fiscal Year: 2013
    ..End of Abstract) ..