MECHANISMS OF OXIDANT INDUCED ARTERIAL INFLAMMATION

Brigham And Women'S Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (Adapted from the applicant?s abstract) Dr. Liao?s laboratory has focused for several years on molecular mechanisms whereby various mediators produce pro- and anti-inflammatory effects on vascular endothelial cells. In collaboration with Dr. Libby?s laboratory, Dr. Liao made the observation that nitric oxide can reduce leukocyte adhesion to endothelial cells. Dr. Liao went on to establish a novel molecular mechanism for this phenomenon, inhibition by nitric oxide of nuclear factor kappa B (NF-kB) action. This transcription factor regulates many pro-inflammatory genes invoked in atherogenesis. Part of the inhibition of Nf-KB produced by nitric oxide derives from increased transcription of a principal inhibitor, IKBalpha. In preliminary work, Dr. Liao has localized regions of the IkBalpha promoter region that respond to nitric oxide. A major goal of the current proposal is the identification and characterization of the manner in which nitric oxide regulates IkBa transcription. This project will also test the hypothesis that more recently recognized isoforms of IkB may regulate the activity of the transcription factor differentially in response to diverse stimuli. The last year or so has witnessed an explosion in detailed knowledge of the pathways by which pro-inflammatory stimuli regulate NF-KB-dependent gene transcription by effects on the recently recognized IkB kinase, including the critically important phosphorylation of these inhibitors. Other studies will test the hypotheses that mediators investigated in other projects in this PO-1 regulate the newly recognized vascular NADH oxidase, an important source of reactive oxygen species in the artery wall. Additionally, this project will assess effects of such activating stimuli on the endogenous anti-oxidant pathways in the endothelial cell such as glutathione peroxidase. Dr. Liao?s project will link explicitly with Project 1 by testing the pro-oxidant potential of various components of the micro-organism Chlamydia pneumoniae. Dr. Liao?s project will link conceptually with Project 3, led by Dr. Plutzky, which will explore an interlinked transcriptional regulatory pathway, the peroxisomal proliferation activating receptors (PPAR). As the NF-KB and PPAR pathways likely intersect at several levels, the combined expertise and pooling of reagents should prove synergistic. As hyperglycemia and advanced glycation end products associated with diabetes can produce oxidative stress in endothelial cells, Dr. Liao?s project links to the clinical studies of the mechanisms of arterial dysfunction in diabetics in Project 4 led by Dr. Creager. Project 2 will explore glutathione peroxidase in vitro at the molecular level, while Project 5 will examine the effects of such an activity on arterial vasodilator function in diabetic patients in vivo. Dr. Liao also proposes to test the pro-oxidant potential of endothelin, a mediator to be explored in Project 5 led by Drs. Ganz and Selwyn. To test in vivo correlates of cell culture observations, Dr. Liao will determine the levels of NADH oxidase activity in specimens of human arterial tissue provided by Core B, and evaluate the expression if IkB isoforms in normal and diseased human arterial specimens. Thus, Project 2 provides an essential molecular component to the exploration of pro-oxidant and pro-inflammatory mechanisms of arterial dysfunction, a theme common to many of the allied projects.