MPO, HDL Dysfunction and Cardiovascular Disease

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 DESCRIPTION (provided by applicant): Oxidative stress is implicated in atherogenesis and plaque rupture-the major cause of myocardial infarction (MI) and sudden death. One of the well-characterized sources of oxidative stress is myeloperoxidase (MPO), a heme enzyme that co-localizes with macrophages in human atherosclerotic lesions. Epidemiology studies show that individuals possessing high MPO levels among sequential subjects undergoing diagnostic cardiac catheterization were 15- to 20-fold more likely to demonstrate abnormal coronary angiograms compared with subjects in the lowest quartile. Consistently, individuals with total or subtotal MPO deficiency appear less likely to have CVD development. Importantly, MPO selectively modifies apolipoprotein A-1 (ApoA-I), generating dysfunctional HDL. Here we hypothesize that inhibiting MPO is beneficial to the quality of HDL, which consequently exert atheroprotective effects on the patients. We propose experiments to determine whether MPO is an effective target for reducing atherosclerosis, and to define the roles of MPO on HDL functionality in atherogenesis. We have successfully generated MPO knockout (KO) rabbits using the CRISPR/Cas9 technology. These novel rabbit models will be employed in the present study. We expect establishing a meaningful animal model for the study of MPO biology, gaining novel knowledge, and facilitating the R&D of MPO based therapeutics and diagnostics. Specifically, we will 1) Determine whether MPO is an effective target for reducing atherosclerosis in rabbits; 2) Define the roles of MPO on HDL functionality in atherogenesis using novel rabbit models. It is well documented that mice are not appropriate for the study of MPO biology. Only trace amount of MPO can be detected in atherosclerotic tissues in mice, dwarf to that found in human counterpart. Moreover, mice deficient of MPO showed increased atherosclerosis, opposite to what is observed in humans. This project thus has a unique advantage in resolving such debate (i.e. MPO be atherogenic or anti-atherogenic) by using the novel MPO knockout rabbit models, a species that has been a classic model to study human lipid biology and CVD.