Myeloperoxidase, Chronic Kidney Disease and Atherosclerosis

摘要

ABSTRACT There is a worldwide increase in the incidence and prevalence of chronic kidney disease (CKD) affecting ~11% of adults in the U.S. CKD is a risk factor for CAD, as CKD patients have CAD prevalence of nearly 40% and greater than 10-fold mortality compared to healthy controls. Traditional risk factors are only partially predictive of CAD in CKD subjects, highlighting the need for mechanism-based novel biomarkers that can accurately stratify CAD risk in CKD patients. This proposal directly addresses this critical gap in our diagnostic and prognostic capabilities. We will explore the relationship between CKD, oxidative stress and atherosclerosis in a physiologically relevant animal model with complementary human studies. Evidence strongly implicate a central role for oxidative stress in atherosclerosis but its role in the initiation and progression of CKD- accelerated atherosclerosis has not been systematically investigated. One well-characterized source of oxidative stress is myeloperoxidase (MPO), a heme enzyme that co-localizes with macrophages in human atherosclerotic lesions. While previous studies have attributed MPO oxidation playing a leading role in atherosclerosis, its role in CKD-atherosclerosis has not been systematically elucidated. The overall goals of this proposal are to investigate whether MPO promotes atherogenic risk in CKD. Preliminary studies in a mouse model of CKD strongly demonstrated that MPO oxidative pathway is upregulated in CKD and associated with accelerated atherosclerosis. These observations form the basis of the proposal in which we will test the hypothesis that modulating MPO levels will alter CKD related atherosclerosis in vivo. Together with complementary human studies, we will systematically assess the role of MPO in CKD-accelerated atherosclerosis. The proposed experiments and training plan will enable the PI to gain in depth understanding in cutting edge mass spectrometry and proteomic technologies coupled with intense exposure to vascular biology, transgenic mouse models and clinical research methodology. Specific aims 1) Investigate if MPO plays a central role in CKD-accelerated atherosclerosis mouse models 2) Determine the role of MPO oxidation and lipoprotein profiles in CKD patients with and without CAD These studies will provide evidence for a crucial role for MPO oxidation in the initiation and progression of atherosclerosis in CKD and would facilitate the rational design of interventions to interrupt MPO oxidation.