Oxidation in Inflammation and Cardiovascular Disease

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 DESCRIPTION (Provided by applicant): The overall goal of this continuing Program Project is to develop a better understanding of mechanisms linking oxidation and inflammation to cardiovascular disease (CVD). Projects focus on elucidating mechanisms of distinct yet interconnecting pathways involving both oxidation and inflammation during CVD, and the disruption of hemostatic mechanisms responsible for resolution of inflammatory responses. The Program Project is led by highly productive and experienced investigators and is comprised of 3 interrelated projects and 4 cores. Project 1 explores potential reciprocal regulatory interactions between myeloperoxidase (MPO), an oxidant generating leukocyte-derived heme protein that once released resides on the high density lipoprotein (HDL), and paraoxonase 1 (PON1), an HDL-associated protein that promotes systemic anti-oxidant and atheroprotective effects. Biochemical and genetic studies in mice and humans explore the functional importance of MPO - PON1 interactions in the artery wall and within myocardial tissues following ischemia. Project 2 is thematically linked to both Projects 1 and 3, and explores the role of site-specific S nitrosylation-mediated inactivation of the GAIT (IFN-Gamma-Activated Inhibitor of Translation) translational control system, a pathway limiting inflammation processes. Project 2 similarly extends its studies into the artery wall during atherosclerosis, and into humans through clinical investigations of CVD. It explores the role of MPO-generated specific oxidized phospholipids in plasma, scavenger receptor CD36, and site specific S-nitrosation of GAPDH and other selected targets during GAIT system inactivation during inflammation, atherosclerosis and CVD. Project 3 is similarly interrelated to Projects 1 and 2, and proposes to study how plasminogen (Plg) interacts with multiple distinct Plg receptors to influence macrophage recruitment during inflammatory responses, phagocytosis, and cholesterol deposition and foam cell formation via a pathway that involves induction of 5- lipoxygenase and transcriptional regulation of scavenger receptor CD36. The role of lipoprotein (a), a molecular mimic of Plg, in influencing Plg dependent macrophage foam cell formation, along with the involvement of CD36 and oxidized lipids, will also be explored. Three scientific cores (Human Clinical Materials & Protein Engineering, Mass Spectrometry & Biophysics, and Animal Models) and an Administrative Core, provide multi-project support, significantly strengthening the entire research program. The proposed Program Project will yield greater understanding of oxidative and inflammatory pathways in normal and disease processes, and may help develop new CVD and heart failure risk assessment tools and therapies.